targeted therapy news january 2013

Targeted TherapyNews™

Feature

Innovations in Precision Medicine

As 2012 drew to a close, several key oncology conferences highlighted the most im-portant innovations in targeted oncology therapy—an area often termed “precision medicine” based on our increasing ability to precisely target and treat specific on-

cogeneic mutations and pathways. The Chemotherapy Foundation Symposium, held No-vember 7 to 9, and the 35th Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS), held December 4 to 8, were two such conferences, both focusing on recent rapid developments in targeted therapies. In this issue, we highlight key data and presentations from the two conferences.

(continued on page 30)


Targeted Oncology Therapy in 2012 and 2013: Where Have We Been, Where Are We Going?By Anna Azvolinsky, PhD

Twenty new cancer drugs were approved in 2012, and thousands of new targeted and im-munotherapeutic oncology agents, including

some that will emerge in 2013, are in development. Here we look back at the most important advances in oncology targeted therapy in 2012, and ahead to what to expect for 2013 in key therapeutic areas.

Breast CancerIt has been a productive year for breast cancer trial results and approvals. Two new drugs were

(see page 35)

For the Practicing Oncology Professional

01.13

Solid tumors and hematologic malignancies: Phase III trials

The Personalized Oncology Pipeline:

Bevacizumab

Sara Hurvitz, MD

Research-ers from the Na-

tional Insti-tutes of Health (NIH) have dis-covered a new mechanism of action utilized by poly (ADP-ribose) polymerase (PARP) inhibi-tors in an effort to promote antitumor activity, suggesting that existing and in-development PARP inhibitors differ in how they are able to treat cancer.

The results of the study were pub-lished in the journal Cancer Research.

PARP1 and PARP2 belong to a fam-ily of proteins associated with cellular processes such as chromosome stabil-ity, regulation of apoptosis, cell divi-sion, and transcriptional regulation and differentiation. PARP enzymes are responsible for repairing DNA dam-age caused by environmental stresses and DNA replication errors, including single-strand breaks, by enlisting other proteins to actually repair the damage. These single-strand breaks can become double-strand breaks that are then repaired by a complex that contains BRCA1 and BRCA2, mutations closely linked to breast cancer and ovarian cancer.

Prior to the study, researchers un-derstood that PARP inhibitors—in-cluding drugs such as olaparib and veliparib—worked by blocking PARP enzyme activity, thus preventing the repair of DNA damage and ultimately initiating apoptosis, or cell death, by selectively killing cells with genetic abnormalities.

Feature

Researchers Determine How PARP Inhibitors WorkBy Ben Leach


© SABCS/Todd Buchanan 2012

© SABCS/Todd Buchanan 2012

Yves Pommier, MD, PhD


In this issue...

Melanoma

• �Nab-paclitaxel extends PFS vs standard chemotherapy

Prostate Cancer

• Enzalutamide delays first SRE, improves pain and QoL

• FDA approves earlier use of abiraterone acetate

Hematologic Malignancies

• Ponatinib approved for CML and ALL

Lung Cancer

• �EGFR mutation status and sorafenib in NSCLC

Colorectal Cancer

• Biomarker may predict response to bevacizumab in mCRC

Thyroid Cancer

• FDA approves cabozantinib to treat medullary thyroid cancer

INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages.

www.PROVENGE.com

OVERALL SURVIVAL BENEFIT OF PROVENGE1,2

100

75

50

25

12 24

Time From Randomization (Months)

36 48 60 72

Surv

ival

(%)

21.7 months21.7

months

00

25.8 months

HR=0.775 (95% CI: 0.614, 0.979)

P=0.032

PROVENGE (n=341)

Control* (n=171)

22.5%RISK

REDUCTION

100

75

50

25

12 24

Time From Randomization (Months)

36 48 60 72

Surv

ival

(%)

21.7 months21.7

months

00

25.8 months

HR=0.775 (95% CI: 0.614, 0.979)

P=0.032

PROVENGE (n=341)

Control (n=171)

First-line treatment for men with asymptomatic or minimally symptomatic metastatic CRPC (NCCN Category 1 recommendation)3

1st

and only

1st

line

Extends median survival beyond 2 years1>2 years

EXTEND SURVIVAL

In advanced prostate cancer

First and only FDA-approved immunotherapy for advanced prostate cancer

TREAT FIRST LINE WITH PROVENGE TO

Prostate cancer cell

PROVENGE- activated T cells

Activated T cell attacks prostate cancer

T-cell activation

PROVENGE

Resting T cell

Prostate cancer cell

Amplify

Activate

Attack

Data originally published in The New England Journal of Medicine: Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

*64% of patients in the control group, following progression, crossed over to a nonrandomized, open-label protocol to receive an investigational autologous immunotherapy made from cryopreserved cells.

5654-1_Targeted_Therapy_Spread_Nov_L1.indd 1-2 10/18/12 5:21 PM

PROVENGE® (sipuleucel-T)Suspension for Intravenous Infusion Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION •For Autologous Use Only. •TherecommendedcourseoftherapyforPROVENGEis3completedoses,givenat

approximately2-weekintervals. •Premedicatepatientswithoralacetaminophenandanantihistaminesuchas

diphenhydramine. •Beforeinfusion,confirmthatthepatient’sidentitymatchesthepatientidentifierson

the infusion bag. •Do Not Initiate Infusion of Expired Product. •InfusePROVENGEintravenouslyoveraperiodofapproximately60minutes.

Do Not Use a Cell Filter. •Interruptorslowinfusionasnecessaryforacuteinfusionreactions,dependingon

theseverityofthereaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS

•PROVENGE is intended solely for autologous use.

•Acute infusion reactions(reportedwithin1dayofinfusion)included,butwerenotlimitedto,fever,chills,respiratoryevents(dyspnea,hypoxia,andbronchospasm),nausea,vomiting,fatigue,hypertension,andtachycardia.Incontrolledclinicaltrials,71.2%ofpatientsinthePROVENGEgroupdevelopedanacuteinfusionreaction.

Incontrolledclinicaltrials,severe(Grade3)acuteinfusionreactionswerereportedin3.5%ofpatientsinthePROVENGEgroup.Reactionsincludedchills,fever,fatigue,asthenia,dyspnea,hypoxia,bronchospasm,dizziness,headache,hypertension,muscleache,nausea,andvomiting.Theincidenceofsevereeventswasgreaterfollowingthesecondinfusion(2.1%vs0.8%followingthefirstinfusion),anddecreasedto1.3%following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalizedwithin1dayofinfusionformanagementofacuteinfusionreactions. NoGrade4or5acuteinfusionreactionswerereportedinpatientsinthe PROVENGE group.

Closelymonitorpatientswithcardiacorpulmonaryconditions.Intheeventofanacuteinfusionreaction,theinfusionratemaybedecreased,ortheinfusionstopped,dependingontheseverityofthereaction.Appropriatemedicaltherapyshouldbeadministered as needed.

•Handling Precautions for Control of Infectious Disease. PROVENGE is notroutinelytestedfortransmissibleinfectiousdiseases.Therefore,patientleukapheresis material and PROVENGE may carry the risk of transmitting infectious diseasestohealthcareprofessionalshandlingtheproduct.Universalprecautionsshould be followed.

•Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapyorimmunosuppressiveagents(suchassystemiccorticosteroids)givenconcurrentlywiththeleukapheresisprocedureorPROVENGEhasnotbeenstudied.PROVENGEisdesignedtostimulatetheimmunesystem,andconcurrentuseofimmunosuppressiveagentsmayaltertheefficacyand/orsafetyofPROVENGE.Therefore,patientsshouldbecarefullyevaluatedtodeterminewhetheritismedicallyappropriatetoreduceordiscontinueimmunosuppressiveagentspriortotreatmentwith PROVENGE.

•Product Safety Testing. PROVENGE is released for infusion based on the microbial andsterilityresultsfromseveraltests:microbialcontaminationdeterminationbyGramstain,endotoxincontent,andin-processsterilitywitha2-dayincubationtodetermineabsenceofmicrobialgrowth.Thefinal(7-dayincubation)sterilitytestresultsarenotavailableatthetimeofinfusion.IfthesterilityresultsbecomepositiveformicrobialcontaminationafterPROVENGEhasbeenapprovedforinfusion,Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism,performantibioticsensitivitytestingonrecoveredmicroorganisms,and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONSBecauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinpractice.

ThesafetyevaluationofPROVENGEisbasedon601prostatecancerpatientsinthePROVENGEgroupwhounderwentatleast1leukapheresisprocedureinfourrandomized,controlledclinicaltrials.Thecontrolwasnon-activatedautologousperipheralbloodmononuclear cells.

Themostcommonadverseevents,reportedinpatientsinthePROVENGEgroupatarate≥15%,werechills,fatigue,fever,backpain,nausea,jointache,andheadache.Severe(Grade3)andlife-threatening(Grade4)adverseeventswerereportedin23.6%and4.0%ofpatientsinthePROVENGEgroupcomparedwith25.1%and3.3%ofpatientsinthecontrolgroup.Fatal(Grade5)adverseeventswerereportedin3.3%ofpatientsinthePROVENGEgroupcomparedwith3.6%ofpatientsinthecontrolgroup.

Seriousadverseeventswerereportedin24.0%ofpatientsinthePROVENGEgroupand25.1%ofpatientsinthecontrolgroup.SeriousadverseeventsinthePROVENGEgroupincluded acute infusion reactions (see Warnings and Precautions),cerebrovascularevents,andsinglecasereportsofeosinophilia,rhabdomyolysis,myastheniagravis,myositis,andtumor flare.

PROVENGEwasdiscontinuedin1.5%ofpatientsinStudy1(PROVENGEgroupn=341;Controlgroupn=171)duetoadverseevents.SomepatientswhorequiredcentralvenouscathetersfortreatmentwithPROVENGEdevelopedinfections,includingsepsis.Asmallnumber of these patients discontinued treatment as a result. Monitoring for infectious sequelaeinpatientswithcentralvenouscathetersisrecommended.

EachdoseofPROVENGErequiresastandardleukapheresisprocedureapproximately3dayspriortotheinfusion.Adverseeventsthatwerereported≤1dayfollowingaleukapheresisprocedurein≥5%ofpatientsincontrolledclinicaltrialsincludedcitratetoxicity(14.2%),oralparesthesia(12.6%),paresthesia(11.4%),andfatigue(8.3%).

Table1providesthefrequencyandseverityofadverseeventsreportedin≥5%ofpatientsinthePROVENGEgroupofrandomized,controlledtrialsofmenwithprostatecancer.Thepopulationincluded485patientswithmetastaticcastrateresistantprostatecancerand116patientswithnon-metastaticandrogendependentprostatecancerwhowerescheduledtoreceive3infusionsofPROVENGEatapproximately2-weekintervals.Thepopulationwasage40to91years(median70years),and90.6%ofpatients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

Any Adverse EventChillsFatigueFeverBackpainNauseaJoint acheHeadacheCitrate toxicityParesthesiaVomitingAnemiaConstipationPainParesthesia oralPain in extremityDizzinessMuscle acheAstheniaDiarrheaInfluenza-likeillnessMusculoskeletal painDyspneaEdema peripheralHot flushHematuriaMuscle spasms

591 (98.3)319(53.1)247 (41.1)188(31.3)178(29.6)129(21.5)118(19.6)109(18.1)89(14.8)85(14.1)80(13.3)75(12.5)74(12.3)74(12.3)74(12.3)73(12.1)71(11.8)71(11.8)65(10.8)60(10.0)58(9.7)54(9.0)52(8.7)50(8.3)49(8.2)46(7.7)46(7.7)

186 (30.9)13(2.2)6(1.0)6(1.0)18(3.0)3(0.5)11(1.8)4(0.7)0(0.0)1(0.2)2(0.3)11(1.8)1(0.2)7 (1.2)0(0.0)5(0.8)2(0.3)3(0.5)6(1.0)1(0.2)0(0.0)3(0.5)11(1.8)1(0.2)2(0.3)6(1.0)2(0.3)

291 (96.0)33(10.9)105(34.7)29(9.6)87(28.7)45(14.9)62(20.5)20(6.6)43(14.2)43(14.2)23(7.6)34(11.2)40(13.2)20(6.6)43(14.2)40(13.2)34(11.2)17(5.6)20(6.6)34(11.2)11(3.6)31(10.2)14(4.6)31(10.2)29(9.6)18(5.9)17(5.6)

97 (32.0)0(0.0)4(1.3)3(1.0)9(3.0)0(0.0)5(1.7)0(0.0)0(0.0)0(0.0)0(0.0)7(2.3)3(1.0)3(1.0)0(0.0)1(0.3)0(0.0)0(0.0)2(0.7)3(1.0)0(0.0)3(1.0)3(1.0)1(0.3)1(0.3)3(1.0)0(0.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

(Table 1 continued on next page.)

5654-1_Targeted_Therapy_Spread_Nov_BS_L1.indd 1 10/18/12 5:22 PM

Cerebrovascular Events.Incontrolledclinicaltrials,cerebrovascularevents,includinghemorrhagicandischemicstrokes,werereportedin3.5%ofpatientsinthePROVENGEgroupcomparedwith2.6%ofpatientsinthecontrolgroup.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

HypertensionAnorexiaBonepainUpper respiratory tract infectionInsomniaMusculoskeletal chest painCoughNeck painWeight decreasedUrinary tract infectionRashSweatingTremor

45(7.5)39(6.5)38(6.3)38(6.3)

37(6.2)36(6.0)

35(5.8)34(5.7)34(5.7)33(5.5)31(5.2)30(5.0)30(5.0)

3(0.5)1(0.2)4(0.7)0(0.0)

0(0.0)2(0.3)

0(0.0)3(0.5)2(0.3)1(0.2)0(0.0)1(0.2)0(0.0)

14(4.6)33(10.9)22(7.3)18(5.9)

22(7.3)23(7.6)

17(5.6)14(4.6)24(7.9)18(5.9)10(3.3)3(1.0)9(3.0)

0(0.0)3(1.0)3(1.0)0(0.0)

1(0.3)2(0.7)

0(0.0)2(0.7)1(0.3)2(0.7)0(0.0)0(0.0)0(0.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

*Controlwasnon-activatedautologousperipheralbloodmononuclearcells.

©2012DendreonCorporation. Allrightsreserved.June2012. PrintedintheU.S.A. Dendreon,theDendreonlogo,andPROVENGE are registered trademarks of Dendreon Corporation.P-A-05.12-144.01

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011. 3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. V.3.2012. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed April 26, 2012.

5654-1_Targeted_Therapy_Spread_Nov_BS_L1.indd 2 10/18/12 5:22 PM

In This Issue...4

Targeted Therapy News • 1.13

38 Research Profile: Exploring the Breast Cancer Genome

EvidEncE-BasEd OncOlOgy40 Precision Medicine and the Rapidly Approaching

Future of Cancer Management By Maurie Markman, MD

Features News

Departments

MElanOMa11 �Nab-Paclitaxel Extends PFS Versus

Standard Chemotherapy in Metastatic Melanoma

By Ben Leach

PROsTaTE cancER11 Enzalutamide Delays First SRE,

Improves Pain and QoL in Patients With Metastatic Prostate Cancer

By Bonnie Gillis

15 FDA Approves Earlier Use of Abiraterone Acetate

By Jason M. Broderick

HEMaTOlOgic MalignanciEs15 Ponatinib Approved for CML

and ALL

lUng cancER16 �EGFR Mutation Status and Sorafenib

in NSCLC By Bonnie Gillis

cOlOREcTal cancER17 Biomarker May Predict

Response to Bevacizumab in mCRC

By Ben Leach

THyROid cancER17 FDA Approves Cabozantinib to

Treat Medullary Thyroid Cancer By Ben Leach

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HealthcareCommunications

Targeted18 Innovations in Precision Medicine

24 Researchers Determine How PARP Inhibitors Work

By Ben Leach PARP inhibitors may differ

in how they are able to treat cancer.

30 Targeted Oncology Therapy in 2012 and 2013: Where Have We Been,

Where Are We Going? By Anna Azvolinsky, PhD Twenty cancer drugs were

approved in 2012, and more are in development in 2013.

35 The Targeted Oncology Pipeline: Solid Tumors and Hematologic Malignancies

Phase III trials Key trials for 2013.

Visit Health-Adviser.com to join today!

HealthAdviser is a growing community of healthcare experts who share insights and earn honoraria through participation in focus groups, one-on-one interviews, and online surveys.

HealthAdviser is the healthcare professional community of HRA – Healthcare Research & Analytics, a leading market research firm serving the pharmaceutical, biotechnology, and medical device industries. Along with Targeted Therapy News, HRA is part of the MJH & Associates family of companies.

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Evan M. Hersh, MD

Karim Fizazi, MD

Charles J. Ryan, MD

Jorge E. Cortes, MD

Tony S. Mok, MD

David O. Bates, PhD

Richard Pazdur, MD

Yves Pommier, MD, PhD

Sara Hurvitz, MD

Highlights of the most important developments in targeted therapies from key conferences.

From the Publisher 5


as we enter into our second year of publication, we are delighted to announce that Targeted Therapy News will now be published six times a year. The decision to increase our frequency was spurred both by the extremely positive feedback from our readers and by the rapid pace of developments in

oncology. Also with this issue, Targeted Therapy News reaches a broader circulation of physicians, nurses, and pathologists. In each issue we will focus additional attention on clinical trial updates, conference highlights, and exclusive interviews with leading physicians.

Along with our sister publication, the peer-reviewed The International Journal of Targeted Therapies in Cancer, and our website, TargetedHC.com, our aim is to keep the oncology community up to date on the newest developments in targeted, personalized medicine in oncology. TargetedHC.com provides tailored content focused on next-generation therapeutics and their molecular targets. Our website provides information on the latest news in targeted therapies while creating a clinical and peer-to-peer platform for our visitors.

As always, we welcome your feedback and suggestions for our targeted therapy publications. Please contact our editorial staff with your comments at [email protected].

Thank you for reading.

Peter Ciszewski

Delivering More Targeted News

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HealthAdviser is the healthcare professional community of HRA – Healthcare Research & Analytics, a leading market research firm serving the pharmaceutical, biotechnology, and medical device industries. Along with Targeted Therapy News, HRA is part of the MJH & Associates family of companies.

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Why should I join HealthAdviser?As a registered HealthAdviser member, you...

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A n updated analysis of the phase III EMILIA trial showed that the antibody-drug conjugate T-DM1 significantly extended survival compared with the combination of lapatinib/capecitabine in women with HER2-positive, un-

resectable, locally advanced or metastatic breast cancer. The data were presented at the European Society for Medical Oncology (ESMO) 2012 Congress.

At a median follow-up of about 20 months, T-DM1 reduced the mortality risk by 32% (hazard ratio [HR] = 0.68; 95% CI, 0.55-0.85; P <.001), with a 6-month differ-ence favoring T-DM1. Median overall survival (OS; death from any cause) was 30.9 months for T-DM1 versus 25.1 months for lapatinib/capecitabine, which experts called “unprecedented” in metastatic breast cancer.

“The significant improvement in progression-free survival and overall survival as well as the favorable safety suggest that T-DM1 should be an important thera-peutic option in the treatment of metastatic HER2-positive breast cancer,” said lead author Sunil Verma, MD, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada. The results of the EMILIA trial were simultaneously published online in The New England Journal of Medicine to coincide with Verma’s presentation.

The OS data presented at ESMO were from the second EMILIA interim analy-sis, with a data cutoff of July 31, 2012, when more than 50% of targeted survival events had occurred. Final OS data are expected in 2014.

T-DM1 is an antibody-drug conjugate linking trastuzumab to the potent che-motherapy DM1, allowing intracellular delivery of chemotherapy that is said to

In less than a decade, lung cancer has been transformed from a dis-ease broadly characterized by tumor

histology to an intricate molecular mo-saic in which at least 10 genetic driver mutations or abnormalities have been identified in adenocarcinomas alone.

D. Ross Camidge, MD, PhD, direc-tor of the Thoracic Oncology Clinical Program at the University of Colorado Denver, has been at the forefront of ef-forts to identify driver mutations and develop therapies that target those ab-normalities.

In 2009, Camidge helped define the impact of rearrangements in the ana-plastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) (J Thorac Oncol. 2009;4[12]:1450-1454). He then played a leading role in the clini-

cal trial that led to the FDA’s approval last year of crizotinib (Xalkori), the first ALK inhibitor for advanced NSCLC.

This year, the Bonnie J. Addario Lung Cancer Foundation honored Camidge with its fifth annual lectureship award during the 13th International Lung Cancer Congress. In announcing the award, the foundation leadership said Camidge is “a relentless advocate of molecular testing, redefining the stan-

Feature

Targeted Multikinase Inhibitors Pazopanib and Cabozantinib Explored in Thyroid and Other CancersBy Ben Leach

Feature

Molecular Challenges in Lung CancerBy Ben Leach

Two targeted agents—pazopanib and cabozantinib—are under investigation for different types of thyroid cancer, and while the therapies have not yet been approved for these indications, researchers are already trying to deter-

mine the best way to integrate them into existing treatment regimens.Several trials are investigating pazopanib (Votrient)—a small-molecule

multikinase inhibitor that is already approved to treat advanced renal cell carcinoma and soft-tissue sarcoma—for use in advanced thyroid cancer. A phase II trial is under way to assess the use of pazopanib in combination with the chemotherapy agent paclitaxel and radiation therapy in patients with anaplastic thyroid cancer, a very rare and aggressive form that accounts for about 1% of all cases of thyroid cancer.

(continued on page 42) (continued on page 48)


D. Ross Camidge, MD, PhD

Feature

T-DM1 Improves Overall Survival in HER2-Positive Breast Cancer

By Bonnie Gillis

For the Practicing Oncology Professional

In this issue...

Breast Cancer• Everolimus plus tamoxifen in

hormone-resistant mBC• One year of adjuvant

trastuzumab remains standard of care

• Subcutaneous trastuzumab vs standard IV infusion

• Research identifies four distinct subtypes of breast cancer

Lung Cancer• Positive results with first ALK

inhibitor• Dacomitinib improves PFS in

NSCLC

Melanoma• Pathway that causes

chemotherapy resistance in melanoma cells identified

• Long-term data show significant survival improvement for ipilimumab

Renal Cell Carcinoma• Phase III safety data for

tivozanib• Pazopanib shows better

tolerance in advanced RCC

Hematologic Malignancies• Current and emerging strategies

for managing relapsed/refractory Hodgkin lymphoma

• Switching therapy following suboptimal response in chronic myleogenous leukemia

11.12T-DM1

(See page 30)

Emerging Personalized Therapies Offer Hope in Multiple Myeloma


Researchers are working to turn multiple myeloma into a chronic disease.

Kenneth C. Anderson, MD

TTN_11'12.2.indd 1 11/16/12 3:29 PM

N O R T H A M E R I C A N E D I T I O N

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TargetedTherapiesThe International Journal of

in Cancer

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Clinical ArticlesThe Evolving Role of Brentuximab Vedotin in the Management of CD30-Positive Lymphoma Francisco J. Hernandez-Ilizaliturri, MD

Prepare to Attack JAK: Managing Myeloproliferative Neoplasm Constitutional SymptomsHolly L. Geyer, MD, and Ruben A. Mesa, MD

Trastuzumab Emtansine (T-DM 1): A Novel and Effective Immunoconjugate for the Treatment of HER2+ Breast CancerJiali Li, MD, Alexa Glencer, and Hope S. Rugo, MD

Clinical Trial Profile: NeuVax Vaccine for the Prevention of Breast Cancer Recurrence in the PRESENT Trial

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– Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage

– Sepsis occurring during neutropenia has resulted in discontinuation of treatment and, in rare cases, death

• DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow

• Hand-foot syndrome (HFS) may occur during therapy with DOXIL®

– Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required

– HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier• The reaction was mild in most patients, resolving in 1 to 2 weeks• The reaction can be severe and debilitating in some patients, resulting in

discontinuation of therapy• DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation• DOXIL® can cause fetal harm when used during pregnancy• Because of the potential for serious adverse reactions in nursing infants,

discontinue nursing during treatment with DOXIL®.• Recall reaction has occurred with DOXIL® administration after radiotherapy• DOXIL® may interact with drugs known to interact with the conventional

formulation of doxorubicin HCl

• In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) ≥20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%)– In addition, 19% vs 52.3% reported alopecia (all grades)– Grade 3/4 hematologic ARs reported in ≥5% (DOXIL® vs topotecan, respectively)

were neutropenia (12% vs 76%) and anemia (6% vs 29%)• In patients with multiple myeloma, the most common all-grade ARs ≥20% (DOXIL®

plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%) , pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%)– In addition, 19% vs <1% reported HFS

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Please see Brief Summary of full Prescribing Information on the following pages.

INDICATIONS• DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease

has progressed or recurred after platinum-based chemotherapy• DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of

patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATIONBOXED WARNINGSCardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution • The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to

congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2

– Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose

– Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy

• Acute infusion-related reactions including, but not limited to, fl ushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate– Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like

infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use

– The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions

• Severe myelosuppression may occur• DOXIL® dosage should be reduced in patients with impaired hepatic function• Accidental substitution has resulted in severe side effects. Do not substitute

for doxorubicin HCl on a mg per mg basis

CONTRAINDICATIONS• Patients with a history of hypersensitivity reactions to a conventional doxorubicin

formulation or the components of DOXIL®

ADDITIONAL SAFETY INFORMATION• Cardiac function should be carefully monitored

– Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy

– For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefi t of therapy must be weighed against the risk of myocardial injury

– In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defi ned as absolute decrease ≥15% over baseline or a ≥5% decrease below institutional lower limit of normal)

• Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® – In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet

count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL®

– In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE

Prescribe With CONFIDENCE. The brand you’ve long relied on remains an important therapeutic option for you and your patients.

DOXIL® Is Now Available.

We Are COMMITTED long-term to ensuring a reliable supply of DOXIL®.

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DOXIL®(doxorubicin HCl liposome injection) for intravenous infusionBRIEF SUMMARY. Please see Full Prescribing Information.

INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for thetreatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-basedchemotherapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment ofpatients with multiple myeloma who have not previously received bortezomib and have received at least one priortherapy.

CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have ahistory of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL[see Warnings and Precautions].

WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardialdamage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin,particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currentlyrecommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who havereceived radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agentssuch as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included incalculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered afterdiscontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should beadministered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should becarefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury isendomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have beenused to monitor cardiac function during anthracycline therapy. Any of these methods should be employed tomonitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiacinjury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the riskof myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL atstarting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, orbetween 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study,cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction(LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than theinstitutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity andcongestive heart failure (CHF) are in the table below.

Table 1: Number of Patients With Advanced Breast CancerDOXIL (n=250)

Patients who Developed Cardiotoxicity 10(LVEF Defined)

Cardiotoxicity (With Signs & Symptoms of CHF) 0Cardiotoxicity (no Signs & Symptoms of CHF) 10

Patients With Signs and Symptoms of CHF Only 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiacfailure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema andpulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% ineach group. LVEF decrease was defined as an absolute decrease of ≥15% over baseline or a ≥ 5% decreasebelow the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in therandomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms:flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest andthroat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Inmost patients, these reactions resolve over the course of several hours to a day once the infusion is terminated.In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treatedwith DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because ofinfusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusionreactions have been reported. Medications to treat such reactions, as well as emergency equipment, should beavailable for immediate use. The majority of infusion-related events occurred during the first infusion. Similarreactions have not been reported with conventional doxorubicin and they presumably represent a reaction to theDOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimizethe risk of infusion reactions [see Full Prescribing Information].Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring isrequired during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With therecommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reductionor delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection,neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted indiscontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancertherapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination withother agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppressionwas generally moderate and reversible. In the three single-arm studies, anemia was the most commonhematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia(24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologicadverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), andthrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF(or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-relatedKaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease orconcomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at therecommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reactionexperienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% ofpatients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients(1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data onmyelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling,pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of thepatients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skintoxicity. HFS toxicity grades are described in Dosage and Administration section [see Full PrescribingInformation]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% ofpatients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to twoweeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manageHFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and mayrequire discontinuation of treatment.Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy.Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman.There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy,or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to thefetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of thedrug must be considered. Women of childbearing potential should be advised to avoid pregnancy duringtreatment with Doxil. [see Full Prescribing Information].Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-inducedtoxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration ofdoxorubicin HCl.Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequentlyand at a minimum prior to each dose of DOXIL [see Warnings and Precautions].ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in moredetail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [seeWarnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [seeWarnings and Precautions]The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting,diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. Themost common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in ClinicalTrials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovariancancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma. Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, theadverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflectthe rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXILin ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma.Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treatedwith DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in arandomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days(range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanicand other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared totopotecan.

Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian CancerDOXIL Patients Topotecan Patients

(n = 239) (n = 235)Neutropenia

500 - <1000/mm3 19 (7.9%) 33 (14.0%)<500/mm3 10 (4.2%) 146 (62.1%)

Anemia6.5 - <8 g/dL 13 (5.4%) 59 (25.1%)<6.5 g/dL 1 (0.4%) 10 (4.3%)

Thrombocytopenia10,000 - <50,000/mm3 3 (1.3%) 40 (17.0%)<10,000/mm3 0 (0.0%) 40 (17.0%)

Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study ofDOXIL compared to topotecan.

Table 3: Ovarian Cancer Randomized StudyNon-Hematologic DOXIL (%) Topotecan (%)Adverse Reaction treated treated10% or Greater (n = 239) (n =235)

All Grades All Grades grades 3-4 grades 3-4

Body as a WholeAsthenia 40.2 7.1 51.5 8.1Fever 21.3 0.8 30.6 5.5Mucous Membrane 14.2 3.8 3.4 0DisorderBack Pain 11.7 1.7 10.2 0.9Infection 11.7 2.1 6.4 0.9Headache 10.5 0.8 14.9 0

DigestiveNausea 46.0 5.4 63.0 8.1Stomatitis 41.4 8.3 15.3 0.4Vomiting 32.6 7.9 43.8 9.8Diarrhea 20.9 2.5 34.9 4.2Anorexia 20.1 2.5 21.7 1.3Dyspepsia 12.1 0.8 14.0 0

Nervous Dizziness 4.2 0 10.2 0

RespiratoryPharyngitis 15.9 0 17.9 0.4Dyspnea 15.1 4.1 23.4 4.3Cough increased 9.6 0 11.5 0

Skin and AppendagesHand-foot syndrome 50.6 23.8 0.9 0Rash 28.5 4.2 12.3 0.4Alopecia 19.2 N/A 52.3 N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer withdoses administered every four weeks.

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombo phlebitis, hypotension, cardiacarrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic andLymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia,hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia,sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash,exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. SpecialSenses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTALSUBSTITUTION1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage maylead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a startingdose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500-550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of otheranthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiactoxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who arereceiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-relatedreactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, backpain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated withDOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusionis terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious andsometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported.Medications to treat such reactions, as well as emergency equipment, should be available for immediateuse. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [seeWarnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should notbe substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].

DOXIL® (doxorubicin HCl liposome injection)

Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every threeweeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combinationgroup were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age,58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 4 lists adverse reactions reportedin 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.

Table 4: Frequency of treatment emergent adverse reactions reported in ≥ 10% patients treated for multiplemyeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRATerminology.

Adverse Reaction DOXIL + bortezomib Bortezomib(n=318) (n=318)

Any Grade Grade Any Grade Grade(%) 3 4 (%) 3 4

Blood and lymphatic system disordersNeutropenia 36 22 10 22 11 5Thrombocytopenia 33 11 13 28 9 8Anemia 25 7 2 21 8 2General disorders and

administration site conditionsFatigue 36 6 1 28 3 0Pyrexia 31 1 0 22 1 0Asthenia 22 6 0 18 4 0Gastrointestinal disordersNausea 48 3 0 40 1 0Diarrhea 46 7 0 39 5 0Vomiting 32 4 0 22 1 0Constipation 31 1 0 31 1 0Mucositis/Stomatitis 20 2 0 5 <1 0Abdominal pain 11 1 0 8 1 0Infections and infestationsHerpes zoster 11 2 0 9 2 0Herpes simplex 10 0 0 6 1 0InvestigationsWeight decreased 12 0 0 4 0 0Metabolism and Nutritional disordersAnorexia 19 2 0 14 <1 0Nervous system disordersPeripheral Neuropathy* 42 7 <1 45 10 1Neuralgia 17 3 0 20 4 1Paresthesia/dysesthesia 13 <1 0 10 0 0Respiratory, thoracic and

mediastinal disordersCough 18 0 0 12 0 0Skin and subcutaneous

tissue disordersRash** 22 1 0 18 1 0Hand-foot syndrome 19 6 0 <1 0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathyperipheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.

**Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular,rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience: The following additional adverse reactions have been identified during post approval useof DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not alwayspossible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal andConnective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rarecases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemiawith and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin andsubcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermalnecrolysis have been reported.DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interactwith drugs known to interact with the conventional formulation of doxorubicin HCl.USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category D [see Warnings and Precautions]. : DOXIL isembryotoxic at doses of 1 mg/kg/day in rats and is embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (bothdoses are about one-eighth the 50 mg/m2 human dose on a mg/m2 basis). Embryotoxicity was characterized byincreased embryo-fetal deaths and reduced live litter sizes. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs, includinganthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursinginfants from DOXIL, discontinue nursing during treatment with DOXIL.Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL incombination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of ageor older. No overall differences in safety or efficacy were observed between these patients and younger patients.Hepatic Impairment: The pharmacokinetics of DOXIL has not been adequately evaluated in patients with hepaticimpairment. Doxorubicin is eliminated in large part by the liver. Thus, DOXIL dosage should be reduced in patientswith impaired hepatic function [see Full Prescribing Information].Prior to DOXIL administration, evaluation of hepatic function is recommended using conventional clinicallaboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin [see Full Prescribing Information].OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, andthrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patientwith hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

Manufactured by:Ben Venue Laboratories, Inc.Bedford, OH 44146Manufactured for:Janssen Products, LP Horsham, PA 19044© Janssen Products, LP 2010

Revised September 2012

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.K08D121020

TM

An ALZA STEALTH®

Technology Product

DOXIL® (doxorubicin HCl liposome injection)

Editorial Board10


Jame abraham, MdSection of Hematology/OncologyMary Babb Randolph Cancer CenterWest Virginia UniversityMorgantown, WV

Ross abrams, MdDepartment of Radiation OncologyRush University Medical CenterChicago, IL

alex a. adjei, Md, PhdDepartment of MedicineRoswell Park Cancer InstituteBuffalo, NY

lawrence afrin, MdDivision of Hematology/OncologyMedical University of South CarolinaCharleston, SC

sanjiv s. agarwala, MdDivision of Oncology/HematologySt. Luke’s Hospital & Health NetworkBethlehem, PA

nita ahuja, MdSurgery & OncologyThe Johns Hopkins HospitalBaltimore, MD

lowell anthony, MdSection of Hematology & OncologyLouisiana State UniversityNew Orleans, LA

david artz, Md, MBaInformation Systems Memorial Sloan-Kettering Cancer CenterNew York, NY

J. Robert Beck, MdFox Chase Cancer CenterPhiladelphia, PA

Tomasz Beer, MdProstate Cancer ProgramOregon Health & Science University Cancer InstitutePortland, OR

E. Roy Berger, MdNorth Shore Hematology AssociatesEast Setauket, NY

Ralph v. Boccia, MdCenter for Cancer and Blood DisordersBethesda, MD

Jeffrey Bumpous, MdDivision of Otolaryngology-HNS University of LouisvilleLouisville, KY

Barbara a. Burtness, MdHead and Neck Medical OncologyFox Chase Cancer CenterPhiladelphia, PA

John caton Jr, MdMedical OncologyWillamette Valley Cancer CenterEugene, OR

Emily chan, Md, PhdVanderbilt UniversityNashville, TN

Helen chan, MdGI Surgical OncologyLakeland Regional Cancer CenterLakeland, FL

Tarek chidiac, MdMid-Ohio Oncology/Hematology Inc, dbaThe Mark H. Zangmeister CenterColumbus, OH

Patrick Wayne cobb, MdHematology-Oncology Centers of the Northern RockiesBillings, MT

Ezra E. W. cohen, MdSection of Hematology/OncologyUniversity of ChicagoChicago, IL

Richard cohen, MdCohen Hufford Koltzova MedicalSan Francisco, CA

allan cohn, MdRocky Mountain Cancer CenterDenver, CO

sandra cuellar, Pharmd, BcOPDepartment of Pharmacy PracticeUniversity of Illinois at ChicagoChicago, IL

Mary daly, Md, PhdPopulation ScienceFox Chase Cancer CenterPhiladelphia, PA

don dizon, MdProgram in Women’s OncologyWomen & Infants HospitalProvidence, RI

Habib doss, MdTennessee Oncology, PLLCNashville, TN

anthony Elias, MdBreast Cancer & Sarcoma ProgramsUniversity of Colorado Cancer CenterAurora, CO

Fadi Estephan, MdMedical OncologyHutchinson ClinicHutchinson, KS

Evelyn Fleming, MdGynecologic OncologyDartmouth-Hitchcock Medical CenterLebanon, NH

Michele Fox, MdPathologyMyeloma Institute for Research & TherapyUniversity of Arkansas for Medical SciencesLittle Rock, AR

sharon l. Francz, BHa, Bs, ONational Coalition of Oncology Nurse NavigatorsRockville, MD

david R. gandara, MdDivision of Hematology and OncologyUC Davis Cancer CenterSacramento, CA

leonard g. gomella, MdDepartment of UrologyThomas Jefferson UniversityPhiladelphia, PA

andre goy, Md, MsJohn Theurer Cancer Center Hackensack University Medical CenterHackensack, NJ

david graham, MdClinical Trials Carle Clinic AssociationUrbana, IL

gregory griffin, MdDivision of Hematology/OncologyAlfred I. duPont Hospital for ChildrenWilmington, DE

Reuben guerrero, MdDivision of Oncology/HematologyStraub Clinic & HospitalHonolulu, HI

Mahendra gupta, MdMedical OncologyInnovis HealthFargo, ND

daniel Hamstra, Md, PhdPediatric Radiation OncologyGenitourinary Radiation OncologyUniversity of MichiganAnn Arbor, MI

Robin Hanson, Md, PhdCardinal Kids Cancer CenterSt. John’s Mercy Medical CenterCreve Coeur, MO

Roy s. Herbst, Md, PhdDivision of Medical OncologyYale School of MedicineNew Haven, CT

William Hocking, MdHematology/OncologyMarshfield ClinicMarshfield, WI

clifford a. Hudis, MdBreast Cancer Medicine ServicesMemorial Sloan-Kettering Cancer CenterNew York, NY

dennie Jones, Jr, MdNew Mexico Cancer Care AllianceUniversity of New MexicoAlbuquerque, NM

Emad Kandil, MdDepartment of SurgerySection of Endocrine & Oncological SurgeryTulane Cancer CenterNew Orleans, LA

song Kang, MdVirginia Oncology AssociatesSentara Careplex HospitalHampton, VA

gary lyman, Md, MPH, FRcP(Edin)Duke University Medical CenterDurham, NC

david g. Maloney, Md, PhdClinical Research DivisionFred Hutchinson Cancer Research CenterSeattle, WA

Maurie Markman, MdClinical Affairs & Medical Oncology Cancer Treatment Centers of AmericaPhiladelphia, PA

Robert Meister, MdArlington-Fairfax HematologyArlington, VA

Wilson Mertens, MdCancer ServicesBaystate HealthSpringfield, MA

Joseph Mikhael, MdDivision of Hematology/OncologyDepartment of Internal MedicineMayo ClinicScottsdale, AZ

Mohamed Mitwally, MdDepartment of Obstetrics & Gynecology University of MinnesotaMinneapolis, MN

Janaki Moni, MdMichiana Hematology OncologySouth Bend, IN

Hyman Muss, MdUniversity of Vermont and Vermont Cancer CenterHematology Oncology UnitBurlington, VT

leigh neumayer, MdIntegrated Breast ProgramHuntsman Cancer InstituteSalt Lake City, UT

anthony nguyen, MdMedical OncologyComprehensive Cancer Centers of Nevada-SienaHenderson, NV

Joyce a. O’shaughnessy, MdDivision of Breast Cancer ResearchTexas Oncology/US OncologyDallas, TX

daniel a. Osman, MdBreast Cancer SurgeonMiami, FL

andrew l. Pecora, MdJohn Theurer Cancer Center Hackensack University Medical CenterHackensack, NJ

Edith a. Perez, MdDepartment of Hematology/OncologyMayo ClinicJacksonville, FL

Roman Perez-soler, MdDivision of OncologyAlbert Einstein College of MedicineBronx, NY

daniel P. Petrylak, MdGenitourinary Oncology SectionColumbia University Medical CenterNew York, NY

aarati Rao, MdDivision of Pediatric Hematology/OncologyUniversity of South AlabamaMobile, AL

douglas Reding, Md, MPHMarshfield CenterMarshfield, WI

John Rhee, MdMedical Oncology & Hematology, PCYale-New Haven HospitalNew Haven, CT

adam i. Riker, MdCancer ServicesOchsner Cancer InstituteNew Orleans, LA

steven Rosen, MdRobert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, IL

Richard J. Rosenbluth, Md John Theurer Cancer CenterHackensack University Medical CenterHackensack, NJ

Oliver sartor, MdDepartment of UrologyTulane Cancer CenterNew Orleans, LA

lee schwartzberg, MdThe West ClinicMemphis, TN

Maureen sheehan, MdKansas City Cancer CenterKansas City, MO

Edibaldo silva, Md, PhdDivision of Surgical OncologyEppley Cancer Center University of Nebraska Medical Center Omaha, NE

david spigel, Md Lung Cancer ProgramThe Sarah Cannon Research InstituteNashville, TN Kellie sprague, MdBone Marrow TransplantationTufts Medical CenterBoston, MA

Richard Tenglin, MdOncology AssociatesRapid City Regional HospitalRapid City, SD

J. Tate Thigpen, MdDivision of Medical OncologyUniversity of MississippiJackson, MS

Katherine Tkaczuk, MdMedicine & Oncology University of Maryland Cancer CenterBaltimore, MD

debu Tripathy, MdWomen’s Cancer ProgramUniversity of Southern CaliforniaLos Angeles, CA

Philip villiotte, MdSpectrum Medical GroupScarborough, ME

Roland Walter, Md, PhdClinical Research DivisionFred Hutchinson Cancer Research Center Seattle, WA

Ronald Walters, Md, MBa, MHaMedical Operations & InformaticsBreast Medical OncologyMD Anderson Cancer CenterHouston, TX

Richard Wein, MdDepartment of Otolaryngology-Head & Neck SurgeryTufts Medical CenterBoston, MA

H. Jack West, MdThoracic Oncology ProgramSwedish Cancer InstituteSeattle, WA

James Wheeler, MdRadiation Oncology ProgramGoshen Center for Cancer CareGoshen, IN

andrew d. Zelenetz, Md, PhdDepartment of MedicineMemorial Sloan-Kettering Cancer CenterNew York, NY

Paul Zeltzer, MdNeurosurgeryDavid Geffen School of MedicineUniversity of California, Los AngelesLos Angeles, CA

Jeffrey Zonder, MdHematology/OncologyKarmanos Cancer CenterDetroit, MI

HealthcareTargeted

Targeted Therapies: Melanoma

News


Nab-Paclitaxel Extends PFS Versus Standard Chemotherapy in Metastatic Melanoma By Ben Leach

Targeted Therapies: Prostate Cancer

A phase III trial that compared nab-paclitaxel (nab-P; Abraxane) with dacarbazine (DTIC) in patients

with metastatic malignant melanoma (MMM) found that nab-P nearly doubled the median time to progression-free survival (PFS), suggest-ing that it might be a superior treatment op-tion when compared with the standard che-motherapy regimen currently offered to pa-tients.

The international ran-domized, open-label CA033 trial enrolled chemotherapy-naïve patients with stage IV MMM who had no brain metastases. Patients were randomized to re-ceive either 150 mg/m2

of nab-P on days 1, 8, and 15 every 4 weeks (n = 264) or 1000 mg/m2

of DTIC every 3 weeks (n = 265). PFS was the primary endpoint, with overall sur-vival (OS) serving as the secondary end-point. Other endpoints included objec-tive response rate (ORR), disease control rate (DCR), and safety and tolerability.

sus 27%, respectively (P = .004).In the CA033 study, the most com-

mon grade >3 treatment-related ad-verse events that were reported in >10% of patients were neuropathy, which was reported in 25% of nab-P patients and 0% of DTIC patients (P < .001), with a median time to improvement of 28 days, and neutropenia, which was reported in 20% of nab-P patients versus 10% of DTIC patients (P = .004).

“Metastatic melanoma presents sig-nificant treatment challenges due in part to limited therapies, low survival rates at diagnosis, and no advances in chemotherapy in 37 years,” said Evan M. Hersh, MD, lead principal investi-gator and professor of Medicine at the University of Arizona College of Medi-cine and Arizona Cancer Center in Tuc-son, and lead author of the CA033 study, in a statement. “Despite advances with targeted treatment and immunothera-pies, there is still a need for new agents including chemotherapy treatments for

The baseline characteristics of pa-tients in both arms were well balanced. The majority of patients were male (66%), had an ECOG performance status of 0 (71%), and had M1c classified disease (65%), meaning either the melanoma had metastasized to other organs or had spread to any distant site with elevated levels of serum lactate dehydrogenase (LDH).

In the intent-to-treat population, the study found that the median PFS among patients who received nab-P was 4.8 months compared with 2.5 months in the DTIC arm (HR = 0.792; 95.1% CI, 0.631-0.992; P = .044). An interim analysis showed that the median OS in the nab-P arm was 12.8 months compared with 10.7 months with DTIC, although those re-sults did not achieve sta-tistical significance (HR = 0.831; 99.9% CI, 0.578-

1.196; P = .094).The authors reported that 73% of pa-

tients received subsequent therapies. An independent analysis found that the ORR was 15% in patients who received nab-P compared with 11% in the DTIC arm (P = .239), and the DCR was 39% ver-

patients with metastatic melanoma.”The results of the trial were presented

at the Society for Melanoma Research 2012 Congress in Hollywood, California.

Nab-paclitaxel is a nanoparticle-sized anticancer compound delivered as an injection that uses human albumin, a water-soluble protein, as a shell to house the active drug. The shell binds to the tumor, and the therapeutic agent is released in a targeted dose, initiat-ing apoptosis. The agent is already ap-proved by the FDA to treat metastatic breast cancer after failure on combina-tion chemotherapy and untreated local-ly advanced non–small cell lung cancer in patients who are not candidates for radiation or surgery. TTN

Hersh E, Del Vecchio M, Brown M, et al. Phase 3,

randomized, open-label, multicenter trial of nab-

paclitaxel (nab-P) versus dacarbazine (DTIC) in

previously untreated patients with metastatic ma-

lignant melanoma (MMM). Pigment Cell Melanoma Res. 2012;25(6): 863.

An analysis of the phase III AFFIRM trial showed that enzalutamide (Xtandi) significantly delayed the

time to first skeletal-related event (SRE) and significantly improved pain and quality of life (QoL) compared with pla-cebo in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel.

Enzalutamide is an oral androgen re-ceptor inhibitor that targets multiple steps on the androgen receptor path-way. Based on the results of the AFFIRM trial, the FDA recently approved enzalu-

tamide to treat patients with mCRPC who were previously treated with docetaxel.

The AFFIRM trial in-cluded 1199 patients with progressive mCRPC who had received ≤2 regimens of docetaxel. Participants were randomized 1:1 to enzalutamide or placebo. Demographic charac-teristics were well bal-anced between the two treatment arms. Median age was 69 years. Medi-

Enzalutamide Delays First SRE, Improves Pain and QoL in Patients With Metastatic Prostate CancerBy Bonnie Gillis an pain score was >4 in

28% of patients. Ninety percent had bone me-tastasis, and 43% had re-ceived bisphosphonates. Overall results of the AF-FIRM study showed that enzalutamide prolonged survival and risk of death versus placebo. Median survival was 18.4 months with enzalutamide ver-sus 13.6 months with placebo, representing a 37% reduction in risk of death.

At the 2012 ESMO Congress, Karim Fi-zazi, MD, Institut Gustav Roussy, Ville-juif, France, reported a subanalysis of AFFIRM focused on the effect of enzalu-tamide versus placebo on SRE, pain, and QoL. The subanalysis showed that enzalutamide significantly delayed time to first SRE: a median of 16.7 months with enzalutamide versus 13.3 months with placebo, representing a 31% reduc-tion in risk of SRE (P = .0001).

The distribution of first SRE showed a generally favorable effect of enzalu-tamide, with fewer patients experi-encing radiation to the bone (20% for

Table. Phase III Results Comparing Nab-Paclitaxel With Dacarbazine

Treatment Median OS Median PFS ORR

Nab-paclitaxel 12.8 mo 4.8 mo 15%

Dacarbazine 10.7 mo 2.5 mo 11%

P value .094 .044 .239mo = months; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

1111

Karim Fizazi, MD

Evan M. Hersh, MD

®


JAK targeted to make a difference

Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

150

100

50

0

-50

-100

Ch

ang

e Fr

om

Bas

elin

e (%

)

IMP

RO

VE

ME

NT

WO

RS

EN

ING

50% Improvement

Upper 50th Percentile Upper 50th Percentile

Placebo (n = 145)Jaka� (n = 145)

Upper 50th Percentile Upper 50th Percentile

Placebo (n = 153)Jaka� (n = 155)

80

60

40

20

0

-20

-40

-60

-80

Ch

ang

e Fr

om

Bas

elin

e (%

)

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

IMP

RO

VE

ME

NT

WO

RS

EN

ING

35% Reduction

Jaka� ® (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

JAK2

JAK1

* Intermediate or high-risk MF.

REDUCEsplenomegaly and symptoms of MF

REGULATEJAK signalingJAK signaling

References: 1. Jaka� Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

Jaka� is a registered trademark of Incyte Corporation.© 2012, Incyte Corporation. All rights reserved. RUX-1160C 07/12

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information• Treatment with Jakafi can cause hematologic adverse reactions,

including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jaka� . Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

Please see Brief Summary of Full Prescribing Information on the following page.

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache

• Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions. Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jaka� . Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

and initiate appropriate treatment promptly• A dose modifi cation is recommended when administering Jakafi

with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and ef� cacy

• There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modi� ed Myelo� brosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jaka� group and 16.5 in the placebo group.1,2

Jaka�

At Week 24, signi� cantly more patients receiving Jaka� vs placebo had

— A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a

— A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b

Reductions in spleen volume and improvements in TSS were seen with Jaka� in both JAK2V617F-positive patients and JAK2V617F-negative patients, relative to placebo2

Visit www.jaka� .com/explorefor more information on Jaka� and MF, plus valuable educational resources.

Jaka� demonstrated superior reductions in spleen volume andimprovements in symptom scores at Week 241,2,a,b

In these charts, each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

74240ha_d.indd 1 7/30/12 4:42 PM

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya

Jakafi Placebo (N=155) (N=151)Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3%Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.A complete blood count must be performed before initiating therapy with Jakafi [see Dosage andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a registered trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011-2012 Incyte Corporation. All rights reserved.Issued: June 2012 RUX-1040a

74240ha_d.indd 2 7/30/12 4:42 PM

Targeted Therapies: Hematologic Malignancies

News


15

The FDA has approved ponatinib (Iclusig) for the treatment of pa-tients with chronic myeloid leu-

kemia (CML) and Philadelphia chro-mosome–positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant (R/I) to prior tyrosine kinase inhibitors (TKIs).

Ponatinib was approved three months earlier than expected, under the FDA’s accelerated approval program. It is a third-generation TKI that has demon-strated potent activity against native and mutated BCR-ABL and other kinas-

es, as well as in subtypes with a T315I gene mutation.

“The availability of Iclusig will improve the outcome of many patients with CML and Philadelphia-positive ALL who are resistant or intolerant to prior TKI ther-apy. It is an effective therapy that meets an unmet medical need and has to date overcome all known resistant muta-tions in preclinical studies,” said Jorge Cortes, MD, professor and deputy chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. “Clinical responses to

Iclusig have been observed in patients regardless of their mutation status or stage of disease. It is a valuable new treatment option for leukemia patients.”

Ponatinib, an oral multikinase inhibi-tor, generated significant responses in more than 50% of patients with certain chronic myeloid leukemia (CML) sub-types, in the phase II PACE trial that was the basis for its approval. The benefit reached 70% for some patients with CML who also harbored a T315I gene muta-tion.

The PACE trial examined 449 pa-

tients with CML who were R/I to dasat-inib (Sprycel) or nilotinib (Tasigna), or for those with the T315I mutation. Pa-tients were divided into cohorts based on whether they were diagnosed with refractory CML in chronic-phase (CP), acute-phase (AP), or blast-phase (BP) CML, and Ph+ALL. Each group was fur-ther categorized according to whether the participants were R/I to prior treat-ment, or whether they exhibited a T315I mutation.

The primary endpoint for the patients with CP-CML was a major cytogenic re-

Ponatinib Approved for CML and ALL

FDA Approves Earlier Use of Abiraterone AcetateBy Jason M. Broderick

Targeted Therapies: Prostate Cancer

The FDA has authorized the use of abiraterone acetate (Zytiga) prior to chemotherapy in patients with

metastatic castration-resistant prostate cancer (mCRPC). The oral agent was originally approved in April 2011 to be used in combination with prednisone in patients with mCRPC following the failure of chemotherapy with docetaxel.

“This expanded indication for Zytiga helps fill a critical medical need, pro-viding physicians an important tool for treating men with metastatic castra-tion-resistant prostate cancer who have not received chemotherapy,” Charles J. Ryan, MD, University of California, San

Francisco, Helen Diller Family Compre-hensive Cancer Center, said in a press release.

Ryan is the lead author of the phase III COU-AA-302 trial that was the basis for the FDA’s decision. Coinciding with the FDA’s approval, results from the COU-AA-302 study were published online in The New England Journal of Medicine.

In the trial, 1088 chemotherapy-naïve patients with mCRPC were randomized 1:1 to either abiraterone or placebo plus prednisone. The trial was unblinded earlier this year, with patients in the placebo arm being offered the option to receive abiraterone.

At 22.2 months’ median follow-up, radiographic progression-free survival

enzalutamide versus 25% for placebo) and spinal cord compression (6% vs 8%), but about 4% in each group experiencing pathological fracture.

Pain was assessed by three methods: Brief Pain Inventory Short Form (BPI-SF, baseline and week 13); self-reported pain diaries at baseline and weekly, including analgesic use and worst pain for 7-day period; and Functional Assessment of Cancer Therapy–Prostate (FACT-P) ques-tionnaire at baseline and week 13.

On the BPI-SF, enzalutamide reduced pain severity; patients taking enzalu-tamide improved pain scores by 7.5%, while those on placebo had worsening pain by 23% (P <.001).

Pain diaries showed pain progression in 28% taking enzalutamide versus 39% of placebo patients (P = .0018). Palliation

(ie, >30% reduction in mean pain score at week 13 vs baseline without a >30% increase in analgesic use) was achieved in 45% of the enzalutamide arm versus 7% of the placebo arm (P = .0079).

On the FACT-P, the median for time to pain progression had not yet been reached in the enzalutamide arm ver-sus 13.8 months in the placebo arm, representing a risk reduction of 44% (P = .0004). The total QoL score on the FACT-P showed that QoL was dra-matically improved in patients taking enzalutamide: 43% had improvement in QoL versus 18% in the placebo arm. Significant improvements were seen in all QoL domains for enzalutamide compared with placebo (P <.001 for all except social/family, which was signifi-cant at P = .006).

Formal discussant of this trial, Eleni Efstathiou, MD, PhD, MD Anderson Cancer Center, Houston, Texas, commended the authors for including QoL and pain alleviation in their analysis of AFFIRM. However, she urged cau-tion when considering the positive results of the subanalysis.

“Although enzalu-tamide clearly reduced the risk of SRE, improved QoL and functionality, and relieved pain and delayed pain pro-gression, there is no evidence in this trial that severe pain is reduced. Enzalu-tamide ameliorated bone metastasis in

symptomatic men with CRPC. However, we can-not declare victory, given that severe pain-related events may not be al-tered,” Efstathiou said. She added that better un-derstanding of the mech-anisms involved in bone metastasis could move the field forward. TTN

Fizazi K, Scher HI, Saad F, et

al. Impact of enzalutamide, an

androgen receptor signaling in-

hibitor, on time to first skeletal

related event (SRE) and pain in the phase 3 AFFIRM

study. Presented at: 37th European Society for

Medical Oncology Congress; September 28-Octo-

ber 2, 2012; Vienna, Austria. Abstract 896O.

was 16.5 months with abiraterone versus 8.3 months with placebo (hazard ratio [HR] = 0.53; 95% CI, 0.45-0.62; P <.001). Overall survival (OS) was 27.2 months in the control arm, and had not yet been reached in the abiraterone arm (HR = 0.75; 95% CI, 0.61-0.93; P = 0.01). The research-ers noted that the OS data did not cross the ef-ficacy boundary.

According to the FDA, the most frequently reported side ef-fects in the abiraterone arm were fa-

tigue, joint swelling or discomfort, swelling caused by fluid reten-tion, hot flush, diarrhea, vomiting, cough, high blood pressure, short-ness of breath, urinary tract infection, and bruising. TTN

Ryan CJ, Smith MR, de Bono

JS, et al. Abiraterone in meta-

static prostate cancer without

previous chemotherapy [pub-

lished online ahead of print

December 10, 2012]. N Engl J Med. doi:10.1056/NEJMoa1209096.

Charles J. Ryan, MD

Eleni Efstathiou, MD, PhD

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya

Jakafi Placebo (N=155) (N=151)Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3%Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.A complete blood count must be performed before initiating therapy with Jakafi [see Dosage andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a registered trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011-2012 Incyte Corporation. All rights reserved.Issued: June 2012 RUX-1040a

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Targeted Therapies: Lung Cancer

Results of the phase III MISSION trial presented at the 2012 ESMO Congress showed that third- or

fourth-line treatment with sorafenib did not improve overall survival (OS) in pa-tients with advanced non–small cell lung cancer (NSCLC). A post-hoc biomarker analysis of MISSION sug-gested that patients with EGFR-mutant tumors may benefit from treat-ment with sorafenib, but KRAS mutation status was not predictive of re-sponse.

“Mutated EGFR is a potent predictor for gefi-tinib. There was a hint in the biomarker analysis that it may be predictive for sorafenib, but inter-pret these data with cau-tion,” said lead author Tony S. Mok, MD, Chinese University of Hong Kong. “The sample size is small, it was a subgroup analysis, and an explor-atory analysis only.”

MISSION was a multinational, double-blind, placebo-controlled, randomized phase III trial comparing sorafenib plus best supportive care versus best sup-portive care alone as third- or fourth-line therapy in an unselected popula-tion with NSCLC. The study enrolled 703 patients who were randomized 1:1 to either 400 mg of oral sorafenib twice daily or placebo.

Median overall survival was com-parable between the sorafenib and placebo arms (248 vs 253 days; P = .4687), and thus the trial failed to reach its primary endpoint. Statisti-

cally significant improvements with sorafenib were demonstrated with sev-eral secondary endpoints, including median progression-free survival (PFS; P <.0001), time to disease progression (P <.0001), overall response rate (P <.001), and disease control rate (P <.0001).

Although the primary results were negative, the researchers conducted a

mutational analysis in-volving 347 patients to determine if some pa-tients might benefit from sorafenib. In the analysis subgroup, EGFR muta-tions were detected in 26% and KRAS mutations in 20%, and were well balanced between the two study arms.

The EGFR mutation analysis included 44 pa-tients from the sorafenib group and 45 from the placebo group who had

mutated EGFR in tumor or plasma, and 122 in the sorafenib group and 136 in the placebo group with wild-type EGFR.

A significant PFS ben-efit was observed for sorafenib in patients with mutated EGFR: me-dian PFS was 2.7 months with sorafenib versus 1.4 months with placebo (hazard ratio [HR] = .27; 95% CI, .16-.46; P <.001). PFS was also significant-ly better with sorafenib in wild-type EGFR patients versus the placebo group: median PFS of 2.7 months versus 1.5 months, respectively

(HR = .62; 95% CI, .48-.82; P <.001).

However, me-dian OS was sig-nificantly better in EGFR-positive patients who re-ceived sorafenib, but no difference was found between the study arms in the wild-type group. Median OS was 13.9 months with sorafenib versus 6.5 months with placebo for EGFR-positive patients (HR = .48; 95% CI, .30-.76; P <.002). In patients with wild-type EGFR, median OS was 8.3 months in the treatment arm versus 8.4 months with placebo (HR = .92; 95% CI, .70-1.21; P <.559).

The lack of benefit in the wild-type EGFR group suggests a potential benefit

of EGFR mutational sta-tus as a biomarker, Mok noted.

With KRAS-mutated or KRAS wild-type NSCLC, however, no significant PFS or OS benefit was ob-served for sorafenib.

“Based on current data, we hypothesize that EGFR mutation is a predictive biomarker for sorafenib in treatment of patients with advanced NSCLC. It is possible that the OS outcome was

biased by the unbalanced use of post-study tyrosine kinase inhibitor. KRAS mutation did not appear to influence re-

sponse to sorafenib. A negative interac-tion was observed for both PFS and OS. Sorafenib resulted in more favorable PFS outcomes than placebo in patients with both KRAS-mutant and wild-type tumors,” Mok said.

In a press conference at ESMO 2012, Luis Paz-Ares, MD, Hospital Virgen del Roc, Seville, Spain, commented on the next step for researchers. “There is no clear explanation for the benefit of sorafenib in the EGFR-mutated sub-group. We need to perform the rest of the biomarker analysis before doing a larger trial. This study is hypothesis-gathering.” TTN

Mok TSK, Paz-Ares L, Wu Y-L, et al. Association between tumor EGFR and KRAS mutation status and clinical outcomes in NSCLC patients ran-domized to sorafenib plus best supportive care (BSC) or BSC alone: subanalysis of the phase III MISSION trial. Presented at: 37th European Soci-ety for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract LBA9.

sponse (MCyR), while the outcome was a major hematologic response (MaHR) in the other subtypes. All patients received 45 mg of pona-tinib once daily.

In the CP-CML group, 54% of patients (144 of 267) achieved MCyR, which included 70% of patients with the T315I mutation (45 of 64).

For the AP-CML group, 58% of patients (48 of 83)

reached MaHR; patients in the R/I group achieved a higher response of 60% (39 of 65) than those wih the mutation.

In the BP-CML and Ph+ALL groups, 34% of patients achieved MaHR (32 of 94), with a slight advantage for those without the T315I muta-tion (35% vs 33%, respec-tively).

In a further break-down for patients in the

chronic CP-CML phase, 44% of patients overall (118 of 267) exhibited a complete cytogenic response (CCyR), a figure that includes a 66% CCyR for those with the T315I mutation (42 of 64).

Ponatinib’s label will contain a boxed warning about a possible risk that the drug can cause blood clots and liver toxicity. The most common side effects reported in the PACE trial included high blood pressure, rash, abdominal pain, fatigue, headache, dry skin, constipa-tion, fever, joint pain, and nausea.

“For patients with CML and Philadel-phia-positive ALL who become resistant

or intolerant to TKI treatments, the ap-proval of Iclusig is very positive news,” said Rosalie Canosa, program division director at CancerCare. “The addition of Iclusig to the arsenal of anti-leukemia medicines is a significant development and one that offers hope for patients coping with CML and Philadelphia- positive ALL.”

Approximately 5000 new cases of CML are diagnosed each year in the US. CML patients treated with TKIs can develop resistance or intolerance over time to these therapies. TTN

EGFR Mutation Status and Sorafenib in NSCLCBy Bonnie Gillis

Targeted Therapies: Hematologic Malignancies

Jorge E. Cortes, MD

Tony S. Mok, MD

Luis Paz-Ares, MD

Table. EGFR Mutational Subanalysis of Phase III MISSIOn TrialTreatment Median PFS (mo) Median OS (mo)

EGFR-mutant tumors

Sorafenib (n = 44) 2.7 13.9

Placebo (n = 45) 1.4 6.5

P value <.001 <.002

EGFR wild-type tumors

Sorafenib (n = 122) 2.7 8.3

Placebo (n = 136) 1.5 8.4

P value <.001 <.559mo = months; OS = overall survival; PFS = progression-free survival.

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17

Targeted Therapies: Colorectal Cancer

Targeted Therapies: Thyroid Cancer

Researchers have identified a po-tential predictive marker for survival in cases of metastatic

colorectal cancer (mCRC) treated with bevacizumab (Avastin), suggesting that patients who have the appropriate biomark-er could experience a greater benefit when given the drug, whereas others who do not ex-press the biomarker could be spared from receiving unnecessary therapy.

Bevacizumab is ap-proved by the FDA to treat mCRC when given in combination with a standard chemotherapy regimen of ironotecan, 5-fluorouracil, and leucovorin as a first- or second-line therapy. Although clini-cal trials in patients with mCRC have shown an improvement in survival, no proven predictive markers have yet

a phase III trial in which patients with mCRC received the FOLFOX4 (oxali-platin, leucovorin, and 5-fluorouracil) chemotherapy regimen with or with-out bevacizumab. Those tissue samples were assessed for VEGF165b and total VEGF by immunohistochemistry, and the ratio of the two levels was scored relative to normal tissue samples.

An unadjusted analysis of PFS showed that patients with lower VEGF165b:total VEGF ratios treated with the FOLFOX4 and bevacizumab regimen (n = 24) had a longer median PFS than those who re-ceived FOLFOX4 alone (n = 26; median, 8.0 months vs 5.2 months; P <.02). However, no beneficial effect on PFS was observed in patients with higher VEGF165b:total VEGF ratios when the combination regimen (n = 20) was com-pared with FOLFOX4 alone (n = 27; me-dian, 5.9 months vs 6.3 months).

Although patients with a lower VEGF165b ratio achieved a higher me-dian overall survival (OS) when given FOLFOX4 and bevacizumab (median, 13.6 months) compared with patients who received FOLFOX4 alone (median, 10.6 months), the results did not reach

been identified to determine which pa-tients may experience a greater survival benefit when given the therapy.

The drug works by targeting and blocking VEGF-A, a protein associated with angiogenesis. Since VEGF-A is the product of one gene encoding multiple isoforms, researchers decided to focus

on one splice variant of VEGF-A called VEGF165b that was shown to have antiangiogenesis prop-erties. The hypothesis for the study was that patients with relatively low levels of VEGF165b would respond bet-ter—measured by pro-gression-free survival (PFS)—when treated with bevacizumab. Re-searchers posited that in patients with lower lev-els of VEGF165b, more

of the drug might be able to block the angiogenesis-promoting form of pro-tein VEGF165.

Researchers at the University of Bris-tol used 97 blinded tumor samples from

statistical significance. No difference in OS was observed in the higher VEG-F165b ratio group when comparing the FOLFOX4 and bevacizumab regimen (median, 10.8 months) with FOLFOX4 alone (11.3 months).

“Avastin has shown great potential for a minority of people with bowel can-cer, but it’s been impossible to predict who will benefit from the drug,” said David O. Bates, PhD, lead researcher from the University of Bristol School of Physiology and Pharmacology and lead author of the study. “We now need to look at cancer samples from a larger group of patients about to start taking Avastin and determine if the amount of VEGF165b can accurately identify those patients that will benefit, and so poten-tially open a new treatment option for some people with advanced bowel can-cer.” TTN

Bates DO, Catalano PJ, Symonds KE, et al. Associ-

ation between VEGF splice isoforms and progres-

sion-free survival in metastatic colorectal cancer

patients treated with bevacizumab [published on-

line ahead of print October 25, 2012]. Clin Cancer Res. doi:10.1158/1078-0432.CCR-12-2223.

Biomarker May Predict Response to Bevacizumab in mCRCBy Ben Leach

David O. Bates, PhD

The US Food and Drug Administra-tion today approved cabozantinib to treat medullary thyroid cancer

that has metastasized to other parts of the body.

Medullary thyroid cancer develops in cells in the thyroid gland that make the hormone calcitonin, which helps maintain a healthy level of calcium in the blood. This type of cancer may oc-cur spontaneously or in families with certain genetic mutations that result in one or more cancers of the endocrine system, including the thyroid gland.

The National Cancer Institute esti-mates that 56,460 Americans will be di-agnosed with thyroid cancer and 1780 will die from the disease in 2012. About 4% of thyroid cancers are medullary thyroid cancer, making it one of the rarer types of thyroid cancers.

“Cometriq is the second drug ap-proved to treat medullary thyroid can-

intended to treat a rare disease or con-dition.

Cabozantinib is a kinase inhibi-tor that blocks abnormal kinase pro-teins involved in the development and growth of medullary cancer cells. Patients should not eat for at least 2

hours before and 1 hour after taking cabozan-tinib.

The safety and ef-fectiveness of cabozan-tinib were established in a clinical study in-volving 330 patients with medullary thyroid cancer. Treatment with cabozantinib increased the length of time a patient lived without the cancer progressing (progression-free sur-vival) and, in some pa-tients, reduced the size

of tumors (response rate).Patients who were given cabozan-

tinib lived an average of 11.2 months without tumor growth compared with

cer in the past two years and reflects FDA’s commitment to the development and approval of drugs for treating rare diseases,” said Richard Pazdur, MD, di-rector of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Pri-or to today’s approval and the approval of Ca-prelsa in April 2011, pa-tients with this rare and difficult to treat disease had limited therapeutic treatment options.”

The FDA completed review of cabozan-tinib’s application in six months under the agency’s priority review program. This program provides for an expe-dited six-month review for drugs that may offer major advances in treat-ment or that provide a treatment when no adequate therapy exists. Cabozan-tinib also received orphan-product designation by the FDA because it is

an average of four months in patients receiving a sugar pill (placebo). Results also showed that 27 percent of patients treated with cabozantinib had reduc-tions in tumor size lasting an average of nearly 15 months, while patients who received a placebo saw no reduc-tions. Treatment with cabozantinib did not extend patients’ lives.

The prescribing information for cabozantinib includes a boxed warning alerting patients and healthcare pro-fessionals that severe and fatal bleed-ing and holes (perforations and fistula) in the colon occurred in some patients.

The most common side effects were diarrhea; inflammation or sores of the mouth; redness, pain, or swelling of the digits (hand-foot syndrome); weight loss; loss of appetite; nausea; fatigue; oral pain; graying or loss of hair color; bad taste; new or worsening high blood pressure; abdominal pain and constipation. The most common laboratory abnormalities included in-creases in liver enzymes, low calcium and phosphorus, and decreased white blood cells and platelets.TTN

FDA Approves Cabozantinib to Treat Medullary Thyroid CancerBy Ben Leach

Richard Pazdur, MD

Feature


18

Conference Updates(continued from cover)

18

Novel Formulations and Molecular Characterization of AML Offer Hope and ComplexityBy Devera Pine

Despite advances in the treat-ment of acute myeloid leuke-mia (AML) over the last few

years, survival of patients with the disease remains poor. Recent rapid advances in the characterization of the molecular genetic defects under-lying AML, as well as in novel formu-lations of therapies, are offering hope for improved outcomes, however. In a pre-sentation at the 2012 Chemotherapy Foun-dation Symposium, Gail J. Roboz, MD, as-sociate professor of Medicine and director of the Leukemia Pro-gram at Weill Medi-cal College of Cornell University, New York, NY, reviewed some of the AML therapies in later-stage develop-ment.

AML is the most common form of acute leukemia in adults, with ap-proximately 13,000 new cases diag-nosed each year. Long-term survival is poor, particularly in patients over the age of 60 years, and AML results in ap-proximately 10,000 deaths annually, according to Roboz.

Traditionally, patient-specific fac-tors—age, performance status, and comorbid illnesses—were used to de-termine disease prognosis, but those are giving way to leukemia-specific factors, including cytogenetics, single-gene mutations, antecedent hemato-logic disorders, and secondary AML as prognostic indicators. “Cytogenetics and mutational analyses are driving how we look at the disease,” Roboz said.

AML is now recognized as a geneti-cally highly heterogeneous disease, and although that diversity presents the opportunity to categorize AML by distinct molecular subgroups—possi-bly with personalized treatments for the various mutations—it also pres-ents a challenge in terms of drug de-velopment and clinical trials. “This is a disease of one name, but it’s many different diseases,” Roboz said. “When you’re thinking ahead about personal-izing therapy…it’s going to be an aw-ful lot of personalization and clinical

trial development [to determine] how to make the therapeutic outcomes more than just anecdotal for two peo-ple with a particular set of mutations. It has to be quite carefully considered, and the construction of these person-alized trials is not easy.”

The current treatment paradigm for AML is a very old one, Roboz said, and comprises remission induction followed by consolidation (with 1 to 4 cycles of chemo-therapy or autologous or allogeneic stem cell transplant). Roboz highlighted a number of studies now under way that are aimed at improving the current treatment paradigm, including methods for optimizing “7 + 3” (cy-tarabine [ara-C] com-bined with an anthra-

cycline or anthracenedione). In a multicenter, phase III trial, 652

patients with untreated AML were randomized to one of three induc-

tion regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Com-pared with patients in the DA arm,

patients who received cladribine had a higher rate of complete remission (67.5% vs 56%; P = .01) and overall survival (45% ± 4% at 3 years in the DAC arm vs 33% ± 4% in the DA arm; P = .02).1

Despite these encouraging results, Roboz said that few clinicians add cladribine to the treatment regimen. “This is one of the most perplexing things going on in AML—[this is] a big, randomized study with a clear ben-efit for cladribine, yet nobody does it.” The addition of cladribine, she added, might be something to consider down the road.

Other approaches seek to improve 7 + 3 with the use of novel formula-tions. CPX-351, for instance, is a lipo-somal formulation of cytarabine and daunorubicin in a 5:1 molar ratio.

Elacytarabine conjugates cytarabine with elaidic acid (a naturally occurring fatty acid). Elacytarabine is thought to bypass the transporter protein hENT1 in the leukemic cell membrane, there-by allowing for increased cellular up-take.

Novel agents are also under de-velopment, including vosaroxin, a

first-in-class, anticancer quinolone derivative being studied in the phase III VALOR trial. Patients with first re-lapsed or refractory acute AML will be

randomized to vosaroxin plus cytara-bine versus placebo plus cytarabine. The primary endpoint is overall sur-vival; the secondary endpoints are the complete remission rate and safety and tolerability.

Another late-stage trial is investi-gating the use of decitabine, a DNA demethylating agent, as an induction strategy for patients age 60 years and older with acute AML. The phase II CALGB (Alliance) 11002 trial will look at “real-world” older AML patients, Ro-boz said. The study’s primary endpoint is overall survival, not the complete remission rate, which may indicate whether overall survival for this group of patients depends upon a complete remission.

Finally, two other novel therapies are in development: SGI-110, a dinucleo-tide of decitabine and deoxyguano-sine that increases in vivo exposure/efficacy of decitabine by protecting it from elimination by cytidine deami-nase; and oral azacitidine (AZA-008), now being studied in a phase III trial in AML post-remission and for use post-transplant, Roboz said. (Azaciti-dine is approved as Vidaza for the treatment of all five French-American-British subtypes of myelodysplastic syndromes.) TTN

Holowiecki J, Grosicki S, Giebel S, et al. Cladrib-ine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs sur-vival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012;30:2441-2448.

“When you’re thinking ahead about personalizing therapy…it’s going to be an awful lot of personalization and clinical trial development [to determine] how to make the therapeutic outcomes more than just anecdotal for two people with a particular set of mutations. It has to be quite carefully considered, and the construction of these personalized trials is not easy.”

—Gail J. Roboz, MD

Key Points:

• Cytogenetics, single gene muta-tions, antecedent hematologic disorders, secondary AML are key prognostic indicators

• Cladribine added to daunorubicin and cytarabine during induction prolonged survival

• Novel agents in trials include vosroxin, decitabineSGI-110, azacitidine

Gail J. Roboz, MD

Chemotherapy Foundation Symposium Conference Coverage


19

Choosing a Tyrosine Kinase Inhibitor in CML By Devera Pine

The introduction of tyrosine ki-nase inhibitors (TKIs) for the treatment of chronic myeloge-

nous leukemia (CML) has dramatically changed the course of the disease, so that today there is an 85% chance of a 10-year survival rate for patients treated with imatinib. Now, with five TKIs potentially available for CML, clinicians must weigh the relative ad-vantages and toxicities of each when selecting a course of treatment. In a presentation at the 2012 Chemother-apy Foundation Symposium, Hagop Kantarjian, MD, professor of Medicine, and chairman and professor, Leuke-mia Department, MD Anderson Can-cer Center in Houston, Texas, detailed key considerations for selecting TKI therapy.

Three TKIs are approved for front-line therapy in CML—imatinib, nilo-

tinib, and dasatinib—and a total of five TKIs are available for use in different sequences and circumstances in pa-tients with CML (Table). In addition, omacetaxine, although not a TKI, may have potential for use in combination therapy, Kantarjian said.

Efficacy, toxicities, disease status, salvage status, comorbidities, and cost all should factor into the choice of TKI in CML, Kantarjian said. The

least controversial of those factors, he said, is cost: If a patient is paying out of pocket, imatinib is likely to be the least expensive therapy.

Disease status should play a role in therapy selection: Al-though TKIs have also improved survival in accelerated- and blast-phase CML, that improvement is by no means ideal, Kantar-jian said. For patients in transformation, TKIs should be used in combination and not as single-agent thera-py, he said.

Kantarjian com-pared the use of ima-tinib versus newer TKIs as frontline

therapy in CML. In this setting, the newer TKIs have been shown to re-sult in improved complete cytogenic response (CCyR), major molecular re-sponse (MMR), complete molecular response (CMR), event-free survival (EFS), and transformation rates. On average, the newer TKIs cause less chronic toxicity compared with ima-tinib; the newer therapies also have a cost similar to imatinib.

“For all of these reasons, there is no doubt that second [the newer] TKIs are going to get increasing utilization as frontline therapy for chronic myeloid

leukemia,” Kantarjian said. “What we have to keep in mind is so far, there is no survival benefit. Many patients who fail imatinib can be salvaged effectively with second TKIs.” But Kantarjian said that the choice of wheth-er to use imatinib as frontline therapy ver-sus one of the newer TKIs may come down to cost considerations.

One question that remains to be an-

swered in this area is what price should be paid for what difference in survival or transformation at 5 or 10 years, Kantarjian said. The question will be particularly relevant when

imatinib goes off-patent in the next few years and the price will presum-ably decrease. In three randomized trials of TKIs as frontline therapy (the ENEST-nd, DASISION, and BELA tri-als), on average, the second TKIs re-duced the cumulative incidence of transformation to accelerated phase/blast phase in the first 2 to 3 years from about 5% to approximately 1.5%. The incidence of transformation on study (intent-to-treat population) was reduced by half, from 6% to ap-proximately 3%.

“If second TKIs are effective in re-ducing the incidence of transforma-tion in the first 2 to 3 years, but not later on, what you would expect is at 10 years, a difference in the survival of 3% to 5%,” Kantarjian said. “If second TKIs reduce the incidence of transfor-mation consistently across the years, then you will see a marked difference in the 10-year survival, which will jus-tify their use in frontline therapy re-gardless of the cost.” TTN

Although TKIs have also improved survival in accelerated- and blast-phase CML, that improvement is by no means ideal. Table. TKIs for CML

TKI Frontline Salvage

Imatinib Approved Approved

Nilotinib Approved Approved

Dasatinib Approved Approved

Bosutinib Approved

Ponatinib Approved

CML = chronic myelogenous leukemia; TKI = tyrosine kinase inhibitor.

Hagop Kantarjian, MD

Key Points:

• Generally, second TKIs cause less chronic toxicity vs imatinib

• Choice of imatinib vs second TKIs as frontline therapy may come down to cost

• Long-term data on survival or transformation advantages for second TKIs needed

Study Identifies Potential New Pathways for HNSCC TreatmentBy Lauren M. Green

Scientists now know much more about the genetic landscape of head and neck cancer and hope

that eventually this knowledge will lead the way to new therapies, accord-ing to Aaron D. Tward, MD, PhD, of the Broad Institute of MIT and Harvard. Tward described findings of recent collaborative research on the topic at the 2012 Chemotherapy Foundation Symposium.

Head and neck squamous cell carci-noma (HNSCC) is the sixth most com-

mon non-skin cancer in the world, with approximately 600,000 cases re-ported each year and a mortality rate of 50%. The National Cancer Institute estimates that 52,000 new cases will be diagnosed in the US in 2012, ac-counting for 3% of all cancers.

For this research, Tward, also with the Department of Otology and Laryn-gology at Harvard Medical School and a clinical fellow in those specialties at the Massachusetts Eye & Ear Infirmary in Boston, and colleagues analyzed tu-

mor samples provided by the Univer-sity of Pittsburgh from 92 HNSCC pa-tients. The samples were chosen to be reflective of the normal distribution of patients with these cancers, that is, mostly men and mostly smokers. Of these patients, 89% reported a history of tobacco use and 79% alcohol use; 14% of all tumors and 53% of oropha-ryngeal tumors were found to be posi-tive for human papillomavirus.

Tumor sites also were selected so as to be roughly representative of the

Key Points:

• Mutations implicated in HNSCC include TP53, CD-KN2A, PTEN, PIK3CA, and HRAS

• Trials of PI3K inhibitors may be fruitful in patients with PI3KCA mutations in HNSCC



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Oncolytic ImmunotherapyOncolytic immunotherapy utilizes a modified virus engineered to replicate selectively in tumor cells and to express an immunomodulatory cytokine such as GM-CSF.1, 2 The antitumor effect of the modified virus is based on two proposed modes of action.

Oncolytic: Direct cytotoxic activity due to the replication of the virus and cell lysis of tumor cells.3

Immunotherapy: Tumor cell lysis leads to an indirect induction of a systemic, T-cell mediated, tumor-specific immune response, enhanced by GM-CSF and directed against other tumor cells expressing the same antigen profile.4

Oncolytic Immunotherapy Platform VideoLaunch the mechanism of disease video online, or experience this video virtually through the OncLive AR mobile device app to learn more about Oncolytic Immunotherapy.

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Oncolytic Immunotherapy References:1. Varghese S, Rabkin SD. Oncolytic herpes simplex virus vectors for cancer virotherapy. Cancer Gene Ther. 2002;9(12):967-978.

2. Dranoff G. GM-CSF-secreting melanoma vaccines. Oncogene. 2003;22(20):3188-3192.

3. Hawkins LK, Lemoine NR, Kim D. Oncolytic biotherapy: a novel therapeutic platform. Lancet Oncol. 2002;3(1):17-26.

4. Fukuhara H, Todo T. Oncolytic herpes simplex virus type 1 and host immune responses. Curr Cancer Drug Target. 2007;7(2):149-155.

www.amgenoncology.com/#/our-science/oncolytic-immunotherapy

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2222

Next-Generation Therapy for Multiple MyelomaBy Ben Leach

Immunomodulatory drugs and prote-asome inhibitors have revolutionized the treatment of multiple myelo-

ma by improving patient response and survival. Now, newer and more potent versions of existing therapies are under de-velopment and show-ing considerable prom-ise in early clinical tri-als. At the 2012 Che-motherapy Foundation Symposium, Sundar Ja-gannath, MD, present-ed a comprehensive re-view of several emerg-ing multiple myeloma drugs.1

In terms of immu-nomodulatory agents, pomalidomide appears to be building upon the success of its predecessors, in-cluding lenalidomide. Several clinical trials have confirmed the activity of pomalidomide in patients with mul-tiple myeloma. For example, a study presented at the 2012 American Soci-ety of Clinical Oncology (ASCO) Annual Meeting showed that good responses

were observed when pomalidomide was given with dexamethasone.

In the phase II trial, patients refrac-tory to lenalidomide, bortezomib, or both were randomized to receive

pomalidomide with low-dose dexametha-sone or pomalidomide alone. The overall re-sponse rate in the combination arm was 29% versus 15% with pomalidomide alone. Median progression-free survival was 3.8 months in patients re-ceiving pomalidomide plus dexamethasone, as compared with 2.5 months with pomalid-omide alone (hazard ratio = 0.73; P = .037).

Additionally, pomalidomide appears to work better when given in a 3-weeks-on/1-week-off regimen, according to the results of a study presented at the 2011 American Society of Hematol-ogy (ASH) Annual Meeting.2 Results of the IFM 2009-02 study showed that median time to first response, median

duration of response, and the propor-tion of patients who were alive at least 1 year into the study were all higher in patients who received 3 weeks of pomalidomide followed by 1 week off with weekly dexamethasone compared with patients who received continuous pomalidomide with dexamethasone.

“These responses are durable and meaningful,” said Jagannath, who is di-rector of the Multiple Myeloma Program at the Tisch Cancer Institute at Mount Sinai Medical Center in New York City. The FDA has set an action date for pomalidomide of February 10, 2013.

In addition to the next generation of immunomodulatory therapy, new pro-teasome inhibitors poised to improve upon bortezomib and carfilzomib are also in development. Jagannath highlighted two agents—ixazomib (MLN9708) and marizomib (NPI-0052)—that have yielded promising early data, and clinical trials continuing to assess their efficacy are currently enrolling patients.

Small studies of ixazomib, the first orally available proteasome inhibitor to enter clinical trials, were presented at ASH 2011 and ASCO 2012. These stud-

ies showed activity in heavily pretreat-ed patients with multiple myeloma and suggested that the drug produced durable responses and disease control.

The study presented at ASH showed that six patients had achieved minimal response or better among 36 evaluable patients.3 Additionally, two of those pa-tients achieved a partial response (PR) with duration of disease control of up to 11.3 months. Another 22 patients achieved stable disease.

The study presented at ASCO fur-ther confirmed these positive ixazomib results. Of 53 evaluable relapsed and/or refractory patients, six achieved at least PR. Additionally, a duration of dis-ease control of up to 21.1 months was observed.4

Sundar Jagannath, MD

Key Points:

• Pomalidomide produced durable and meaningful results in refrac-tory disease

• Ixazomib, first oral proteasome inhibitor showed activity in heavily pretreated patients

general HNSCC patient population; thus, most were oral cavity cancers, followed by a substantial proportion of oropharynx cancer samples, and a few from patients with hypopharyngeal or laryngeal tumors.

Investigators used hybrid capture sequencing to compare tumor tissue with nontumor tissue from the same individual. They also compared the to-tal number of mutations in the HNSCC samples with samples from previous tumor studies done at Broad. Tward noted that HNSCC clusters with lung cancer, in that both possess a relatively high number of mutations, sometimes referred to as “the smoking cluster.”

The analysis yielded a very large number of mutations; for example, 5000 genes had at least one mutation, and 1300 had at least two. Tward em-phasized, however, that most of these are not implicated either in promoting or maintaining the cancer. “The vast majority,” he said, “are what we call ‘passengers,’ that is, mutations along-side another mutation that is acting as a driver.” His colleagues at Broad have developed an algorithm to help

researchers distinguish the two, using indicators such as the presence of a mutation in a larger number of tumors and filtering out larger genes, which are more likely to have random mutations.

Tward said their studies confirmed earlier findings implicating TP53, CD-KN2A, PTEN, PIK3CA, and HRAS in head and neck malignancies. Of particular interest, however, are mutations they discovered that have not previously been implicated in these cancers: TP63, IRF6, MED1, and, notably, NOTCH.

Depending on what cell it resides in, NOTCH can act either as an oncogene

(as is the case with acute lymphoblas-tic leukemia) or as a tumor suppres-sor gene in HNSCC and skin cancer. In these latter two, NOTCH is “a critical player in the decision to stop proliferat-ing,” Tward said. When mutations inac-tivate NOTCH, terminal differentiation ceases, causing unrestrained proliferation. To il-lustrate the challenge posed by NOTCH’s dual mechanisms, Tward noted a clinical trial testing a gamma secre-tase inhibitor predicted to inhibit NOTCH in pa-tients with Alzheimer’s disease. The trial was stopped because the drug was causing an increase in squamous cell cancers in the treatment arm.

The researchers also found that mu-tations in genes at the “top of our rank list” for head and neck cancers and de-fects in squamous differentiation are also present in patients with cleft pal-

ate syndromes. “We think this is all re-lated,” said Tward.

“When we add all this up, we come up with wiring patterns in head and neck cancer,” which can be used to inform further studies. He added that

researchers did not find many oncogenes in these tumor sam-ples, an exception be-ing PI3KCA. Tward said that trials with PI3K inhibitors are likely to be fruitful in HNSCC patients, but “only for those who have the mutation.” He also not-ed that investigators did not find EGFR mu-tations, a finding con-sistent with the much larger Cancer Genome Atlas (TCGA) data set. TTN

Stransky N, Egloff AM, Tward AD, et al. The mu-tational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157-1160.

“When we add all this up, we come up with wiring patterns in head and neck cancer.”

—Aaron D. Tward, MD, PhD

Aaron D. Tward, MD, PhD



Feature 2323

“There is reason to believe that this drug may be better than bortezomib and could be given orally,” Jagannath said.

Data on marizomib were also pre-sented at ASH 2011. An interim analysis of 22 patients who received marizomib, the majority of whom were refractory to bortezomib, found that three had achieved PR. Those patients were evalu-able in the active dose range of 0.4 to 0.6 mg/m2, and all were refractory to prior bortezomib. The median time on treat-ment was 1.5 months, and 16 patients (73%) achieved stable disease or better. The authors suggested further investi-gation of the drug in combination with lenalidomide and dexamethasone. Per-haps most significant, Jagannath noted,

is the fact that peripheral neuropathy did not appear to be a side effect, since it is a significant adverse event associ-ated with bortezomib.5 TTN

1. Vij R, Richardson PG, Jagannath S, et al. Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT). J Clin Oncol. 2012;30(suppl; abstr 8016).2. Leleu X, Attal M, Arnulf B, et al. High response rates to pomalidomide and dexamethasone in patients with refractory myeloma, final analysis of IFM 2009-02. Blood. 2011;118(21):812.3. Richardson PG, Baz R, Wang L, et al. Inves-tigational agent MLN9708, an oral proteasome

inhibitor, in patients (pts) with relapsed and/or refractory multiple myeloma (MM): results from the expansion cohorts of a phase 1 dose-escala-tion study. Blood. 2011;118(21):301.4. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple my-eloma (MM). J Clin Oncol. 2012;30(suppl; abstr 8017).5. Richardson PG, Spencer A, Cannell P, et al. Phase I clinical evaluation of twice-weekly mar-izomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple my-eloma (MM). Blood. 2011;118(21):302.

Personalized Therapy and Companion Diagnostics for Lung CancerBy Devera Pine

The era of personalized therapy in lung cancer is here, but as technology for

genetic sequencing continues to improve, the use of companion diagnostics to identify mutations is likely to be replaced by next-generation sequenc-ing, according to Mark G. Kris, MD, chief, Tho-racic Oncology Service at Memorial Sloan-Kettering Cancer in New York, NY.

Kris, speaking at the 2012 Chemotherapy Foundation Sympo-sium, noted that 60% of lung cancers are adenocarcinomas. A good histologic diagnosis is abso-lutely critical for treatment of these cancers, he said.

Testing generally identifies many mutations, but not every mutation is an active driver (Table 1), Kris said. In 2012 alone, however, three new mo-

lecular targets were identified in lung cancer—ROS1, RET, and HER2. “They’re

all actionable—there are drugs in the clinic right now; there are things you can do,” he said. For example, cabozantinib is be-ing investigated for the treatment of RET-positive lung cancer; sunitinib, sorafenib, and vandetanib also target RET. “So these are not theoretical, they’re not maybe it will work in ten years. It’s an amazing story,” Kris said.

At Memorial Sloan-Kettering, genetic sequencing iden-tifies driver mutations in 65% of ad-enocarcinoma specimens, with most mutations in EGFR or KRAS, Kris said. That information helps oncolo-gists select the appropriate treat-ments, and it also sets the stage for research—there are 18 open studies just for non-small-cell lung cancer alone at the center.

For oncologists in community prac-tice, the molecular characteristics of lung cancers can be used to select targeted therapies (Table 2). Routine genotyping at diagnosis for lung can-cer should include EGFR and ALK test-ing as standard for all lung cancers except small cell and squamous cell carcinomas in smokers and large bi-opsy specimens, Kris said. He recom-mended up-front, parallel, multiplex

testing for all mutation drivers, and strongly emphasized that there is no clinical selection or patient profile for adenocarcinoma that can substitute for testing. “I spend a lot of time try-ing to find it—it’s not there,” he said.

“Test, don’t guess.”In the next five years, Kris expects

that next-generation sequencing of all lung cancers for all cancer genes will become commonplace, replac-

ing companion diagnostics, which he says will have limited use. Molecular testing of lung cancers—“It’s cancers, not cancer,” Kris said—has evolved from direct sequencing to identify one gene, to identification of eight genes using systems such as Seque-nom genotyping today, to, in the near future, high-throughput sequenc-ing that can identify more than 200 genes.

“Personalized care for lung cancers is here,” Kris said. “The ‘one size fits all’ treatment era is over.” TTN

“There is reason to believe that [ixazomib] may be better than bortezomib and could be given orally.”

—Sundar Jagannath, MD

Table 2. Lung Cancer Molecular Characteristics and Initial TherapiesMolecular Characteristic Targeted Therapy

EGFR mutation erlotinib

ALK rearrangement crizotinib

KRAS mutation do not treat with erlotinib

HER2 mutation or amplification trastuzumab or lapatinib

MET amplification crizotinib

ROS1 rearrangement crizotinib

RET fusion vandetanib, sunitinib

BRAFV600E vemurafenib

Mark G. Kris, MD

Table 1. Driver Oncogenes Currently Identified in Lung AdenocarcinomasKRAS ROS1

EGFR RET

ALK PI3KCA

HER2 MET

Double Mt MEK1

BRAF NRAS

“So these are not theoretical, they’re not maybe it will work in ten years. It’s an amazing story.”

—Mark G. Kris, MD

Key Points:

• Test for EGFR and ALK at diag-nosis for all lung cancers except small cell and squamous cell carcinomas in smokers and large biopsy specimens

• No clinical selection or patient profile for adenocarcinoma can substitute for testing



However, this study established an-other mechanism of action for PARP inhibitors. Normally, PARP1 and PARP2 are released from DNA once other pro-teins begin the repair process. However, PARP inhibitors are able to trap PARP1 and PARP2 on sites of damaged DNA. These PARP-DNA complexes are more toxic to cells than unrepaired single-strand breaks of DNA that accumulate in the absence of PARP activity, suggest-ing that PARP inhibitors work by “poi-soning” these accumulations of PARP proteins. Additionally, the researchers determined that different PARP inhibi-tors have varying degrees of potency

when it comes to trapping these com-plexes.

“Critical to our research is that, while PARP inhibitors had been assumed to be of equivalent potency based on the de-gree to which they elicit PARP inhibition, we now know that they are not equiva-lent with respect to their potency to trap PARP,” said Yves Pommier, MD, PhD, head of the DNA Topoisomerase/Integrase Group at the National Cancer Institute Center for Cancer Research, in a state-ment. “Our findings suggest that PARP in-hibitors should be categorized according to their potency to trap PARP, in addition to their enzyme inhibition abilities.”

The researchers used PARP assays to assess olaparib, veliparib, and nirapa-rib. They determined that niraparib had the highest potency when it came to trapping PARP, followed by olaparib and veliparib. These findings suggest that these drugs could be classified in two ways: inhibitors that primarily in-hibit PARP enzyme activity but do not trap PARP proteins on DNA; and inhibi-tors that have a dual mechanism of ac-tion and inhibitor PARP enzyme activity while also being able to trap PARP pro-teins.

“Our findings suggest that clinicians who use PARP inhibitors in clinical trials

should carefully choose their drug, be-cause we now suspect results may dif-fer, depending upon the PARP inhibitor used,” said Junko Murai, MD, PhD, Labo-ratory of Molecular Pharmacology, NCI Center for Cancer Research, and lead author of the study, in a statement. “As a next step, we are working to catego-rize other leading PARP inhibitors based upon both PARP trapping and PARP in-hibition.” TTN

Murai J, Huang SN, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;71(21):5588-5599.

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Beyond Bevacizumab: Potential Agents for the Treatment of Ovarian CancerBy Ben Leach

Although the association between vascular endothelial growth fac-tor (VEGF) and ovarian cancer has

been known for quite some time, re-searchers are still struggling to use drugs that inhibit VEGF and angiogenesis in ovarian cancer patients. Bevacizumab appeared promising in clinical trials but has yet to receive FDA approval for treat-ment of the disease, so other agents are being looked at as prom-ising novel therapies.

At the 2012 Chemo-therapy Foundation Sym-posium, Jason A. Konner, MD, a medical oncologist at Memorial Sloan-Ket-tering Cancer Center in New York City, reviewed some of the promising newer agents that may provide a benefit to this difficult-to-treat group of patients.

PARP, poly(adenosine diphosphate [ADP]–ri-bose) polymerase, plays an important role in the repair of single-strand DNA breaks. Sin-gle-strand breaks can become double-strand breaks that are, in turn, repaired by a complex that contains BRCA1 and BRCA2, two genes that have deleteri-ous mutations associated with ovarian cancer. Researchers have theorized that inhibiting the PARP enzyme should se-lectively kill cells with those genetic ab-normalities, so PARP inhibitors are being explored as a treatment option for ovar-ian cancer.

One investigational PARP inhibitor, ve-liparib, is being assessed in a number of clinical trials. In the Gynecologic Oncol-

ogy Group (GOG) 9923 phase I study, car-boplatin and paclitaxel chemotherapy were given in combination with beva-cizumab along with escalating doses of veliparib. Additional trials are currently recruiting patients to assess the efficacy of veliparib in combination with other agents such as topotecan.

“The problem with veliparib is we still don’t know its single-agent efficacy,” Kon-

ner said. “A recent single-agent phase II study was completed by the GOG. It accrued very quickly, and we’re waiting for efficacy data on that.”

Other agents have also shown promising data. Cabozantinib, an oral tyrosine kinase inhibi-tor, is being investigated in a number of different tumor types, including ovarian cancer. “That’s probably the most prom-ising oral TKI for ovarian cancer, having shown the most pronounced re-

sponse rates in early trials,” Konner said.The results of a phase II randomized

discontinuation trial were presented at the American Society of Clinical Oncolo-gy (ASCO) meeting in 2011. The study was halted because a high rate of clinical ac-tivity was observed. The overall response rate among patients with progressive measurable disease at 12 weeks was 24%, and clinical activity was observed regardless of whether patients had previ-ously been treated with platinum-based therapy.1 A randomized phase II trial has been designed to compare cabozantinib with paclitaxel in patients with persis-

tent or recurrent epithelial ovarian, fal-lopian tube, or primary peritoneal cavity cancer.

Another agent under investigation for the treatment of ovarian cancer is aflibercept. Aflibercept is a dual inhibitor of VEGF-A and placental growth factor (PlGF), proteins that promote angiogen-esis. Recently approved for the treatment of metastatic colorectal cancer, studies have shown promising data for the treat-ment of ovarian cancer.

At the 2011 ASCO meeting, results of a phase II multi-institutional study com-bining aflibercept with docetaxel in pa-tients with recurrent ovarian, primary peritoneal, and fallopian tube cancer found that the combination of agents was generally effective. An objective re-sponse rate was confirmed in 25 of 46 (54%; 95% CI, 39%–69%) patients in the trial, with 11 patients achieving a com-

plete response and 4 patients whose dis-ease did not recur for a median of 18.4 months (95% CI, 5.2–31.1) once off treat-ment. The median progression-free sur-vival was 6.43 months and the median overall survival was 26.6 months.2

Konner said that aflibercept mimics bevacizumab in several ways. However, Konner said that the outlook for afliber-cept may be similar to bevacizumab, in that it may struggle to find FDA approval for ovarian cancer.

“It’s unclear what role, if any, afliber-cept will have in the future, since it’s not clear that there are any advantages over bevacizumab,” Konner said. TTN

1. Buckanovich RJ, Berger R, Sella A, et al. Activ-ity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): results from a phase II ran-domized discontinuation trial (RDT). J Clin Oncol. 2011;29(suppl; abstr 5008).2. Coleman RL, Duska LR, Ramirez PT, et al. Phase II multi-institutional study of docetaxel plus afliber-cept (AVE0005, NSC# 724770) in patients with re-current ovarian, primary peritoneal, and fallopian tube cancer. J Clin Oncol. 2011;29(suppl; abstr 5017).

Key Points:

• Cabozantinib showed pronounced response rates in early trials

• Aflibercept being tested but may not have advantages over bevaci-zumab

• Single-agent efficacy trial of veli-parib under way

“[Cabozantinib is] probably the most promising oral TKI for ovarian cancer, having shown the most pronounced response rates in early trials.”

—Jason A. Konner, MD

Jason A. Konner, MD

PARP Inhibitors(continued from cover)


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One Year of Adjuvant Trastuzumab Confirmed as Standard of CareBy Jason M. Broderick

Eight-year follow-up data from the phase III HERA trial has con-firmed that 1 year of adjuvant

trastuzumab (Herceptin) should re-main the treatment standard in wom-en with HER2-positive early-stage breast can-cer. In the HERA study, extending trastuzum-ab therapy to 2 years did not produce an additional benefit. The long-term HERA re-sults were presented at the 2012 European Society for Medical Oncology (ESMO) Con-gress and again at the 35th Annual San An-tonio Breast Cancer Symposium (SABCS).

“You gain nothing from adding the additional year of Herceptin. One year of trastuzumab is now a proven advantage from both a disease-free survival and overall sur-vival viewpoint,” said Brian Leyland-Jones, MBBS, PhD, director of Edith Sanford Breast Cancer Research, Sioux Falls, South Dakota, and one of the au-thors of the HERA study.

HERA accrued 5102 women with locally determined HER2-positive in-vasive early breast cancer between 2001 and 2005. In a press conference at SABCS, Martine J. Piccart, MD, PhD, chief of the Medicine Department at the Jules Bordet Institute in Brus-sels, Belgium, president of ESMO, and chair of the Breast International Group, said, “HER2 status had to be centrally confirmed [IHC 3-positive

or FISH-positive] prior to randomiza-tion.”

Following surgery and physician-determined treatment with chemo-therapy and/or radiotherapy, patients

were randomized to 1 year of trastuzumab (n = 1703), 2 years of trastuzumab (1701), or observation (1698). Trastuzumab thera-py in both treatment arms consisted of an 8-mg/kg loading dose followed by a 6-mg/kg dose every 3 weeks.

After the initial HERA results were presented at the 2005 ASCO Annual Meeting, patients in the obser-vation arm were given

the option to receive trastuzumab. “In 2005, after the release of the strikingly positive results in this trial and two other trials conducted in the United States, 52% of the women random-ized to the observation arm selectively crossed over to receive trastuzumab,” Piccart said.

At 8 years’ median follow-up, dis-ease-free survival (DFS) and overall survival (OS) were similar between the 1- and 2-year treatment arms. The unadjusted hazard ratio (HR) for a DFS event in the longer versus shorter trastuzumab arms was 0.99 (95% CI, 0.85-1.14; P = .86). With the OS com-parison, the HR was 1.05 (95% CI, 0.86-1.28; P = .63).

Piccart said hormone-receptor sta-tus did not affect the efficacy of the

treatment. “Women with HER2-pos-itive breast cancer benefited from trastuzumab whether they had hor-mone receptor-positive tumors or hor-mone receptor-negative tumors.”

The primary cardiac endpoint of symptomatic congestive heart failure was rare and did not vary greatly be-tween the two treatment arms. How-ever, rates of the secondary cardiac endpoint of asymptomatic cardiac dysfunction were higher with 2 ver-sus 1 year of trastuzumab at 7.2% and 4.1%, respectively. Importantly, Piccart noted that treatment cessation most-ly eliminated cardiotoxicity. “Very few women experienced any cardiac event after stopping adju-vant trastuzumab,” Piccart said. “Most of the cardiac events in HERA, like in the other adjuvant trials of trastuzumab, have been reversible.”

With the 1 year trastuzumab regi-men now established, Kent Osborne, MD, commented at the SABCS press confer-ence about the cost implications of the HERA results. “I think the HERA trial is an extremely important one. The reason it’s so important is that you can imag-ine the cost to healthcare if we had to give trastuzumab for two years rather than one. So I was really gratified to see that one year seems to be just as good,” said Osborne, who is director

of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, Texas.

Going forward, Le-yland-Jones said the next challenge will be determining the opti-mal treatment dura-tion of trastuzumab in combination regimens. “We think that we’ve hit the gold standard in terms of [treatment length] of Herceptin as monotherapy. How this

could change is when you have com-binations. So when you have trastu-zumab plus pertuzumab or when you start adding PI3 kinase inhibitors or other drugs, then I think this whole duration question is going to come up again.” TTN

Martine J. Piccart, MD, PhD

Brian Leyland-Jones, MBBS, PhD

Adjuvant Bevacizumab Falls Short in Triple-Negative Breast CancerBy Ben Leach

Patients with triple-negative breast cancer had no statistically signifi-cant improvement in disease-free

survival when they received adjuvant treatment with chemotherapy plus 1 year of bevacizumab compared with patients who received chemotherapy alone, according to the results of the phase III BEATRICE trial presented at the 35th Annual San Antonio Breast Cancer Symposium.

In the open-label, multinational trial, 2591 patients with resected triple-neg-ative invasive early breast cancer were

randomized to receive the investigator’s choice of either standard che-motherapy for four to eight cycles followed by observation (n = 1290) or bevacizumab (5 mg/kg/week equivalent) plus investigator’s choice of standard chemotherapy for four to eight cycles followed by bevaci-zumab monotherapy for a total of 1 year (n =

1301). Researchers were allowed to use taxane-based chemotherapy (>4 cycles), anthracycline-based chemotherapy (>4 cycles), or anthracycline and taxane chemother-apy (3-4 cycles each). Patients were recruited between December 2007 and March 2010. The pri-mary endpoint of the tri-al was invasive disease-free survival (IDFS).

“This endpoint includes other inva-sive cancers, just as a check to make sure that we’re not inducing cancer in another area,” said David Cameron, MD, professor of Oncology at Edin-burgh University in Scotland and lead author of the study.

After a median follow-up of 31.5 months in the chemotherapy-alone arm and 32 months in the bevacizum-ab arm, the 3-year IDFS rate in the bevacizumab arm was 83.7% (95% con-fidence interval [CI], 81.4-86.0) com-pared with 82.7% (95% CI, 80.5-85.0) in

Key Points:

• 1 year of trastuzumab provides disease-free and overall survival advantage

• 2 years offered no additional benefit

• Hormone-receptor status not a factor

• Asymptomatic cardiac dysfunction higher with 2 years

David Cameron, MD

San Antonio Breast Cancer Symposium Conference Coverage


26

Primary endpoint: Progression-free survival

Key secondary endpoint: Overall survival

Buparlisib + fulvestrant Placebo + fulvestrant

Randomization

Pioneering Research of PI3K inhibitors in Malignancies

For more informationwww.clinicaltrials.gov (NCT01610284 and NCT01633060) Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (USA only) Or contact your local Novartis representative

BELLE-2 and BELLE-31

Postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer pretreated with aromatase inhibitor

Archival tumor tissue for analysis of PI3K pathway activation

No more than one prior line of chemotherapy for metastatic disease

ECOG Performance Status ≤2

BELLE-31

Evidence of progression on or after mTOR inhibitor-based treatment

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that buparlisib will become commercially available.

1Additional inclusion/exclusion criteria apply.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

©Novartis 2012Novartis Pharmaceuticals CorporationEast Hanover, NJ 07936 August 2012 G-BKE-1047878

Novartis Pharma AG CH-4002, Basel, Switzerland

BELLE-2 and BELLE-3Two Phase III studies investigating the pan-PI3K inhibitor, buparlisib (BKM120), plus fulvestrant in HR+/HER2– advanced breast cancer

NOW ENROLLING TWO PHASE III STUDIES




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the chemotherapy arm (stratified haz-ard ratio [HR] = 0.87; 95% CI, 0.72-1.07; P = .1810). An interim analysis of over-all survival (OS) was also performed, although only 59% of the required number of events had occurred, so the data were not considered mature. In the bevacizumab arm, 93 deaths had occurred during follow-up compared with 107 deaths in the chemotherapy arm (stratified HR = 0.84; 95% CI, 0.64-1.12; P = .2318).

The adverse events observed in this trial are consistent with other trials of bevacizumab in metastatic breast cancer, Cameron said. Certain grade >3 adverse events appeared more fre-quently in the bevacizumab arm than the chemotherapy arm, including hy-pertension (88 [7%] versus 6 [<1%], re-spectively), a side effect that has been associated with bevacizumab use in past studies. Left ventricular dysfunc-tion and clinical heart failure were

also more common with bevacizumab, although these adverse events were resolved more quickly in the bevaci-

zumab arm compared with the chemo-therapy arm.

“The good news for women is that the outcome of 84% invasive disease-free survival after three years was actu-ally much better than we had originally planned,” Cameron said. “When wom-en go onto the Web and look up what is a very negative image of triple-neg-ative breast cancer, we can at least say [according to] a big worldwide phase III trial, actually the outcomes maybe are not as bad as the older literature sug-gests. But in terms of an improvement in outcome, one year of bevacizumab isn’t the answer.”

Cameron noted that further follow-up is required to determine whether bevacizumab has any potential to im-prove OS. The prespecified OS analysis will be performed when 340 patients in the study have died or all patients have been followed for a median of 5 years, whichever comes first. Cameron said

the results are estimated to become available in late 2013. TTN

Cameron D, Brown J, Dent R, et al. Primary re-sults of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer. Pre-sented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S6-5.

Genetic Alterations Targetable in Triple-Negative Breast CancerBy Ben Leach

Patients with triple-negative breast cancer who have residual disease after receiving neoadju-

vant chemotherapy have a series of genetic alterations that are clinically targetable and may warrant further study with various targeted therapies already available or in development, according to research presented at the 35th Annual San Anto-nio Breast Cancer Sym-posium.

The research showed that triple-negative breast cancer has tre-mendous molecular heterogeneity, with some patients in the study having as many as 6 or 7 different al-terations based on deep sequencing that looked for 182 different onco-genes and tumor sup-pressors known to be al-tered in human cancers.

Approximately 30% of patients with triple-negative breast cancer achieve a pathological com-plete response after receiving neoad-juvant chemotherapy, which leads to a favorable diagnosis. However, the remaining 70% of patients who do not

respond to neoadjuvant chemothera-py have residual disease that leads to worse outcomes.

“In treatment, those patients don’t really have therapeutic options,” said Justin M. Balko, PharmD, PhD, a re-search faculty member who works in the lab of Carlos Arteaga, MD, at the Vanderbilt-Ingram Cancer Center in

Nashville, Tennessee, and lead author of the study. “In particular, they have no targeted therapeutic options. We already know that their tumors were not completely respon-sive to chemotherapy, so using more chemo-therapy down the road may or may not be ef-fective. Our goal was to use state-of-the-art molecular techniques to profile those residu-al tumor cells and see if we could find some

clinically actionable alterations that are present in that residual disease in triple-negative breast cancer.”

Of the 81 tumors that were evalu-ated for oncogenes using next-gen-eration sequencing, 72 (89%) had

mutations in TP53, 22 tumors were MCL1-amplified (27%), and 17 tumors were MYC-amplified (21%). At least 15 additional mutations among the 182 that were tested for were identified in the study.

“This diversity states that we re-ally need to not just look at single biomarkers alone but be able to orga-nize these alterations into pathways,” Balko said.

Using this information, the re-searchers identified clinically tar-getable pathways for which various targeted therapies are either already available or in development. These in-cluded alterations of the PI3K/mTOR pathway in 27 tumors (33%), altera-tions in cell cycle genes in 25 tumors (31%), DNA repair pathway alterations in 16 tumors (20%), Ras/MAPK path-way alterations in 10 tumors (12%), and sporadic growth factor receptor amplifications that occurred in EGFR, IGFR1, FGFR1, KIT, and others.

Additionally, amplifications in the JAK2 locus were identified in 11% (8 of 72) of the patients in whom copy number aberrations were identified among the 81 original tumor samples. Balko said that the survival of patients with this particular amplification is very poor. Since pan-JAK and JAK2 in-

hibitors are currently in clinical trials, Balko said that this is another poten-tial therapeutic target that can be ex-plored.

“I think the timing would be right to not only identify the biomarker but also identify the drug and identify the patients, and hit that in an adjuvant study,” Balko said. “I would be very encouraged to do that based on our data.” TTN

Balko JM, Wang K, Sanders ME, et al. Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in the treatment-refractory residual disease. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S3-6.

“The good news for women is that the outcome of 84% invasive disease-free survival after three years was actually much better than we had originally planned.”

—David Cameron, MD

Key Points:

• 1 year adjuvant bevacizumab did not improve disease-free survival

• Hypertension, left ventricular dysfunction, clinical heart failure more common in bevacizumab patients

• Overall survival analysis still under wayy

Justin M. Balko, PharmD, PhD

Key Points:

• Genetic alterations have been found in PI3K/mTor, Ras/MAPK, EGFR, KIT and others

• Targeted therapies are available or under development for many of the identified mutations





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HDAC Inhibition May Sensitize Triple-Negative Breast Cancer Cells to Certain TreatmentsBy Bonnie Gillis

Preliminary research suggests that in-vitro exposure to a histone deacetylase (HDAC) inhibitor may

sensitize triple-negative breast cancer cells to treatment with a PARP inhibi-tor and cisplatin, according to research presented at the 35th Annual San An-tonio Breast Cancer Symposium.

HDAC inhibitor exposure appears to indirectly cause DNA damage and im-pair the ability of breast cancer cells to repair damaged DNA, thus sensitiz-ing the cells to these two treatments. These effects mimic those in BRCA1-mutated breast cancer cells.

“Triple-negative breast cancer is a particularly aggressive breast cancer that is not susceptible to traditional hormone therapies,” said Kapil N. Bhal-la, MD, chief of Personalized Cancer Medicine at the University of Kansas Cancer Center in Kansas City. “That is why it is important to find new ways of killing triple-negative breast cancer cells.”

DNA repair is essential for survival of certain tumor cells. Previous research has found that proteins such as ATR, CHK1, and BRCA1 are key elements of a cell’s response to DNA damage and subsequent repair of the damage. These three proteins are chaperoned

by heat shock protein 90 (Hsp90).Previous work by Bhalla and col-

leagues showed that treatment with an HDAC inhibitor renders hsp90 inac-tive, thus impeding the DNA damage response involving the three pro-teins. In this way, HDAC inhibition creates an in-tracellular environment that mimics that seen in breast cancer with BRCA1 mutations.

“In simple terms, with HDAC inhibition, we are trying to cause a ‘BRCA-ness’ to confer on triple-negative breast cancer cells the sensitivity to PARP inhibition or plati-num therapy seen in the presence of BRCA1 mu-tations,” Bhalla said.

Their studies showed that inhibition of HDAC3 specifically rendered Hsp90 inactive, consequently inhibiting re-pair of damaged DNA.

“The icing on the cake, so to speak, was that in addition to inhibiting the DNA damage response through deple-tion of DNA repair proteins, HDAC in-hibitors induced DNA damage,” Bhalla

said. “By using HDAC inhibitors, we were targeting the cancer in two ways at once.”

Bhalla and colleagues also analyzed whether treatment with the HDAC inhibitors vorinostat or panobi-nostat would sensitize triple-negative breast cancer cells to PARP inhibition. Combining either of the HDAC in-hibitors with the PARP inhibitor ABT888 result-ed in the death of triple-negative breast cancer cells with or without the BRCA1 mutation. Additionally, vorinostat treatment made the triple-negative breast cancer cells more sus-

ceptible to treatment with cisplatin.“These findings indicate that treat-

ment with pan-HDAC inhibitors vori-nostat or panibostat creates ‘BRCA- ness,’ and in combination with a PARP inhibitor or cisplatin synergistically in-duces apoptosis in human triple-nega-tive breast cancer cells,” Bhalla said.

If these findings are confirmed by further study, Bhalla said that they

could have treatment implications for women with triple-negative breast can-cer and potentially for ovarian cancer, which has a similar genetic makeup to that of triple-negative breast cancer.

“If you have a patient with triple-negative breast cancer who does not have a BRCA1 mutation, you could con-sider a clinical trial with an HDAC in-hibitor in combination with a PARP in-hibitor and cisplatin,” Bhalla said. TTN

Bhalla KN, Rao R, Sharma P, et al. Treatment with histone deacetylase inhibitors creates ‘BRCAness’ and sensitizes human triple nega-tive breast cancer cells to PARP inhibitors and cisplatin. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S3-7.

Kapil N. Bhalla, MD

Key Points:

• HDAC inhibitors may restore sen-sitivity to PARP inhibition or plati-num therapy

• Inhibitors depleted DNA repair proteins and induced DNA dam-age

PD 0332991 Significantly Improves PFS in Patients With Advanced ER+ Breast CancerBy Bonnie Gillis

Combining an investigational agent called PD 0332991 with letrozole as first-line therapy ex-

tended progression-free survival (PFS) in women with advanced estrogen receptor-positive (ER+) breast cancer in a phase II study presented at the 35th Annual San Anto-nio Breast Cancer Sym-posium.

The combination achieved median PFS of 26.1 months compared with 7.5 months for le-trozole alone (P=.006).

PD 0332991 is a novel oral selective inhibitor

of cyclin-dependent kinase (CDK) 4/6, which prevents cellular DNA synthesis by blocking tumor cell cycle progres-

sion.“The dramatic im-

provement in progres-sion-free survival with the combination is very encouraging and clini-cally meaningful,” said Richard S. Finn, MD, associate professor of Medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Ange-les (UCLA) and lead au-thor of the study. “These data represent a poten-

tial major advancement in our efforts to identify new medicines that target patients most likely to have an optimal response.”

Finn said this study validates pre-clinical studies showing that the new compound has significant activity in breast cancer models and acts syner-gistically with hormonal therapy.

The phase II study had two parts. In both parts, postmenopausal women with ER+/HER2- advanced breast can-cer were randomized 1:1 to receive letrozole plus PD 0332991 or letro-zole alone. Part 1 enrolled 66 patients, while part 2 enrolled 99 patients using the same eligibility criteria but also screened tumors for CCND1 amplifica-tion and/or loss of p16 by FISH analysis.

For both parts of the trial, the primary endpoint was PFS. Secondary end-points included response rate, overall survival, safety, and correlative bio-marker studies.

At the conference, pooled results from both part 1 and 2 of the trial were presented, based on a total of 165 pa-Richard S. Finn, MD

Key Points:

• Letrozole and a novel CDK4/6 inhibitor resulted in 63% improve-ment in risk of progression

• AEs: uncomplicated neutropenia, leucopenia, anemia, fatigue

• Phase III trial begins in 2013



29

Eribulin Not Superior to Capecitabine in Previously Treated Metastatic Breast Cancer, but Subgroup Data PromisingBy Bonnie Gillis

Eribulin mesylate failed to show a statistically significant sur-vival benefit compared with

capecitabine in women with previ-ously treated metastatic breast cancer in a phase III trial reported at the 35th Annual San Antonio Breast Cancer Symposium.1 Eribulin achieved similar progression-free survival (PFS) and overall survival (OS) as capecitabine, and failed to show superior-ity over capecitabine, a widely used drug to treat metastatic breast cancer.

On the positive side, this is the first study to demonstrate activity of eribulin in the first-, second-, and third-line setting in metastatic breast cancer, according to lead author Peter A. Kaufman, MD, associate professor of Medicine at the Geisel School of Medicine at Dart-mouth and the Norris Cotton Cancer Center in Lebanon, New Hampshire.

“The study objectives were not met,” Kaufman said. “Although we didn’t show a statistically significant superiority over capecitabine, which was our goal, nu-merically the overall survival with eribu-lin was better than with capecitabine.”

Additionally, subgroup data sug-gested that eribulin improved survival by about 5 months in patients with triple-negative breast cancer versus capecitabine, and this line of study will be pursued further, Kaufman said.

Eribulin—a non-taxane microtubule dynamics inhibitor—was approved in

2010 by the FDA for the treatment of metastatic breast cancer previously treated with an anthracycline and a taxane in either the adjuvant or meta-static setting and at least two cytotoxic chemotherapy treatment regimens for the treatment of metastatic disease. Approval was based on a statistically

significant improve-ment in OS when it was compared with several different treatments currently used to treat the disease.

The present study evaluated use of eribulin versus capecitabine in earlier lines of treatment of metastatic breast cancer. The study ran-domized 1102 patients in a 1:1 ratio receive ei-ther eribulin mesylate 1.4 mg/m2 given on days 1 and 8 of a 21-day cycle,

or capecitabine 1250 mg/m2 adminis-tered orally twice daily on days 1 to 14 of a 21-day cycle. All patients had local-ly advanced or metastatic breast cancer, < 3 prior chemotherapy regimens (< 2 for advanced disease), and prior treat-ment with anthracycline and taxane chemotherapy. Baseline characteristics were well balanced between the two treatment arms.

The results of the study showed that the median OS was 15.9 months for er-ibulin and 14.5 months for capecitabine (HR=0.879; 95% confidence interval [CI], 0.770-1.003; P=.056). Median PFS was 4.1 months and 4.2 months, respectively (HR=1.079; 95% CI, 0.932 – 1.250; P=.305).

Overall response rates were 11% for eribulin and 12% for capecitabine (P=.849). OS for HER2-negative patients was 15.9 months for eribulin and 13.5 months for capecitabine (HR=0.838; 95% CI, 0.715 – 0.983; P=.030).

No new safety concerns emerged in the trial. Adverse events were con-sistent with the established safety profiles of both drugs. Adverse events

occurring in more than 20% included neutropenia (54% for eribulin vs 16% for capecitabine), hand-foot syndrome (<1% vs 45%, respectively), alopecia (35% vs 4%, respectively), leukopenia (31% vs 10%, respectively), diarrhea (14% vs 29%, respectively), and nausea (22% vs 24%, respectively).

Separate trials, also presented at SABCS, examined the use of eribulin in other settings. A phase II, multi-center, single-arm study investigated eribulin plus trastuzumab as first-line therapy for locally recurrent or meta-static HER2-positive breast cancer.2 Preliminary results suggest that the combination appears to have consider-able activity with an acceptable toxic-ity profile. Enrollment in the study is completed, and results are expected by the end of 2013. TTN

1. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracy-clines and taxanes. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Ab-stract S6-6.2. Vahdat, L, Schwartzberg L, Wilks S, et al. Er-ibulin mesylate + trastuzumab for locally recur-rent or metastatic HER2-positive breast cancer: results from a pase 2, multicenter, single-arm study. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract P5-20-04.

“Although we didn’t show a sta-tistically significant superiority over capecitabine, which was our goal, nu-merically the overall survival with eribu-lin was better than with capecitabine.”

—Peter A. Kaufman, MD

tients. In this pooled analysis, median PFS was 26.1 months (95% confidence interval [CI], 12.7 – 26.1) with the com-bination versus 7.5 months (95% CI, 5.6 – 12.6) with letrozole alone, represent-ing a 63% improvement in risk of pro-gression (hazard ratio [HR]=0.37; 95% CI, 0.21 – 0.63, P < .001).

In patients with measurable disease, response rates were 45% for the combi-nation versus 31% for letrozole alone. Clinical benefit rate (complete and par-tial response rates plus stable disease) was 70% versus 44%, respectively.

The most commonly observed treat-

ment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue.

“Importantly this was uncomplicat-ed neutropenia,” Finn said. “There was no evidence of febrile neutropenia.”

A phase III trial of the investigational agent in this patient population will be mounted in 2013.

“The oncology community is look-ing forward to the further evaluation of PD 0332991 in the planned phase III trial and very interested in the poten-tial for this novel CDK4/6 inhibitor to improve the treatment landscape for

patients with advanced breast cancer,” Finn said. TTN

Finn RS, Crown JP, Lang I, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4 – 8, 2012; San Antonio, TX. Ab-stract S1-6.

Peter A. Kaufman, MD

Key Points:

• Eribulin not statistically superior vs capecitabine in improving sur-vival, but numerically superior

• Subgroup data: Eribulin improved survival vs capecitabine in triple-negative breast cancer

These data represent a potential major advancement in our efforts to identify new medicines that target patients most likely to have an optimal response.

—Richard S. Finn, MD


Targeted Oncology Therapy in 2012 and 2013(continued from cover)

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approved: everolimus (Afinitor) for the treatment of women with postmeno-pausal, hormone-receptor positive, HER2-negative advanced disease, and pertuzumab (Perjeta) for the treatment of previously untreated women with HER2-positive metastatic breast cancer.

“Everolimus made a big splash [this year]. We have not seen any drug that has shown a gain in progression-free survival [PFS] in estrogen receptor (ER)-positive breast cancer that is also HER2-negative in more than a decade,” said Sara Hurvitz, MD, director of the breast cancer program at the University of Cal-ifornia, Los Angeles. “This is clearly very meaningful to patients, as it allows us to treat patients without chemotherapy and in a targeted manner.”

According to Hurvitz, everolimus has a more manageable toxicity compared with chemotherapy, although she ac-knowledged that some patients may need dose reductions to manage the mouth sore toxicity seen with use of this drug. Management of mouth sores can be particularly daunting, but with communication and monitoring, this usually can be managed, Hurvitz said. Clinicians need to instruct patients about good oral hygiene and manage-ment of their sores, including letting the doctor know as soon as a mouth sore appears so that the side effect does not get out of control. “With prop-er management, I found it extremely well tolerated.”

Pertuzumab, a novel antibody for HER2-positive breast cancer, was ap-proved in June 2012 to be used in com-bination with trastuzumab (Herceptin) and chemotherapy. Trastuzumab binds and blocks activity of HER2, and pertu-zumab binds at a different location on the HER2 molecule and can prevent the signaling that results from HER2 inter-acting with other HER receptors on the breast cancer cell. The combination aims to prevent some of the resistance that develops as a result of trastuzumab therapy.

“Pertuzumab has yielded an incred-ible improvement in progression-free survival in the frontline, HER2-positive metastatic breast cancer setting,” said Hurvitz.

The challenge with pertuzumab, ac-cording to Hurvitz, is that most women in the United States are diagnosed with earlier stages of HER2 breast cancer and will likely receive trastuzumab earlier in the course of their disease. However, in the pivotal clinical trial for pertuzumab, approximately 90% of the patient popu-lation had never had adjuvant or neo-adjuvant trastuzumab, so the major-ity of patients were truly trastuzumab-

naïve, she said. “The challenge in my own practice is that I am not seeing a lot of first-line HER2-positive metastatic breast cancer.

Moreover, trastuzumab-naïve disease is rare in the metastatic setting in the US,” said Hurvitz. “While I use the per-tuzumab-based regimen in the frontline setting, and have had good results with

it, the prevalence of this patient popula-tion in my own clinic is low, limiting my ability to utilize it.”

The MARIANNE trial, which is exam-ining use of trastuzumab emtansine (T-DM1) in combination with pertuzumab, may also change treatment decisions for HER2-positive metastatic breast cancer. “The outstanding question that we are waiting on is, ‘What is going to happen when the results of the MARI-ANNE trial come out in the next year?’” said Hurvitz. If the MARIANNE trial is positive, treatment of first-line meta-static HER2-positive disease may shift to T-DM1 plus pertuzumab. Results are expected in late 2013 or early 2014.

Results of the EMILIA trial, which test-ed T-DM1 for previously treated HER2-positive disease, were presented at the American Society of Clinical Oncol-ogy (ASCO) 2012 meeting. Roche, which makes T-DM1, filed for FDA approval, and the drug has been granted priority review, with a decision expected by Feb-ruary 26, 2013. T-DM1 has “been a coup for the antibody-drug conjugate tech-nology,” said Hurvitz.

“In the next year we are going to have more data that will change how we view first-, second-, and third-line treatment of HER2-positive breast cancer,” Hurvitz said.

In adjuvant breast cancer treatment, addition of bevacizumab (Avastin) to chemotherapy is currently being ex-plored in several patient populations. The question is whether anti-angio-

genesis therapy has more of an impact on micrometastatic disease compared with established-tumor metastatic dis-ease.

For triple-negative breast cancer (TNBC), the answer appears to be no. The BEATRICE trial presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2012 found that adding bevacizumab to chemo-therapy as an adjuvant therapy after surgery did not improve disease-free survival for patients with TNBC.

Another study, the BETH trial, is currently addressing whether ad-juvant chemotherapy in combination with both trastuzumab and bevacizumab has bet-ter disease-free survival outcomes compared with chemotherapy and trastuzumab in patients with HER2-pos-itive disease. Whether the addition of bevacizumab will benefit HER2-patients “is a big question mark,” according to Hurvitz.

Other ongoing studies that will likely impact breast cancer treatment include the BOLERO-1 and BOLERO-3 trials, both examining the utility of everolimus in HER2-positive breast cancer. The re-sults of both trials could be presented at either the ASCO 2013 conference or SABCS 2013.

Finally, Hurvitz highlighted the re-sults of a phase II trial with PD-0332991 (PD-991) in combination with letrozole in postmenopausal women with ER+, HER2-negative metastatic breast cancer, presented at SABCS 2012. Patients treat-ed with the combination had a median PFS of 26.1 months compared with 7.5 months for those who received letrozole alone. “I don’t think I have ever seen a difference in progression-free survival of that magnitude,” Hurvitz said. The lack of toxicity with the drug was also notable. “It is a phenomenal drug be-cause there are no mouth sores or other issues you see with these drugs on the market, except for a drop in white blood cell count,” she said. PD-991 is an oral, selective inhibitor of the cyclin-depen-dent kinases 4 and 6, which are impor-tant for cell cycle progression and DNA replication. A phase III trial in the same patient population is expected to open in 2013.

Prostate CancerThe availability in the last two years of

novel treatments with diverse mecha-nisms of action has been a real boon for patients, says William K. Oh, MD, chief of the division of Hematology and Medi-cal Oncology at the Mount Sinai School of Medicine and associate director of Clinical Research at the Tisch Cancer In-stitute in New York City.

Abiraterone acetate (Zytiga), an androgen biosynthesis inhibitor, was approved in 2011 for use in patients with metastatic castration-resistant prostate cancer (CRPC) after treatment with docetaxel chemo-therapy. In December 2012, the label was ex-panded to include its use as a first-line CRPC therapy based on the re-sults of the COU-AA-302 trial. “This is not a huge surprise, since there is no reason to believe that

abiraterone would be less effective prior to chemotherapy,” said Oh.

Another androgen pathway drug, enzalutamide (Xtandi), an oral andro-gen receptor signaling inhibitor, was approved in August 2012 for metastatic CRPC after treatment with docetaxel.

“Enzalutamide was approved re-cently and represents a very important advance,” said Oh. “It is well tolerated, associated with a significant survival benefit and is easy for patients to take.” Oh believes that such an agent needs to be investigated in earlier-stage prostate cancer—both newly diagnosed or those with a rising prostate-specific antigen (PSA) level. Treating cancer at either stages of its progression could result in better outcomes.

Oh emphasizes that enzalutamide and other agents must be rigorously tested in earlier-stage patients through clinical trials to understand whether they can be effective in the treatment of earlier disease. One such phase II study is testing the role of enzalutamide as neoadjuvant therapy in patients who are undergoing a prostatectomy for their localized disease (NCT01547299).

Another important therapy, Alpha-radin (radium-223), has demonstrated an overall survival benefit for patients with advanced prostate cancer who also have bone metastasis. “Radium-223 will definitely be a new option that we will have to consider in our therapeutic ar-mamentarium,” said Oh. The question of when to use the agent and which pa-tient sub-populations are most likely to benefit still remain, according to Oh.

Other agents currently in phase III

William K. Oh, MD

“This is clearly very meaningful to patients, as it allows us to treat patients without chemotherapy and in a targeted manner.”

—Sara Hurvitz, MD

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clinical trials include custirsen, an in-fusion drug that blocks the activity of a protein that is overproduced in various cancers including prostate; the BCR-Abl and Src tyrosine kinase inhibitor dasat-inib (Sprycel); the tyrosine kinase inhib-itor cabozantinib; and orteronel, an oral andro-gen synthesis inhibitor. Results from orteronel and cabozantinib phase III trials could read out in 2012, according to Oh. Another drug, tasquini-mod, an oral agent that has various cancer-in-hibiting properties, has intriguing early-stage data, said Oh.

With newly available targeted agents and more that will likely be available soon, the ques-tion of how to integrate new therapies with chemotherapy remains. “I believe that many patients will still benefit from chemotherapy, but avoiding it in those who do not is important to understand,” said Oh.

“It’s an exciting time for this field,” said Oh. “Having been studying prostate cancer for 15 years, I am glad that the re-search is now leading to an explosion of new drugs for patients. It is a reminder that understanding the science behind the disease can lead to practical and real benefits for patients.”

Melanoma“Melanoma continues to be the most exciting cancer with the most advances based on applying scientific knowledge to patient care,” said Antoni Ribas, MD,

PhD, professor of Medicine at the Jons-son Comprehensive Cancer Center at the University of California, Los Ange-les.

Several trials are testing combina-tions of targeted agents for BRAF muta-

tion-positive metastatic melanoma. Following the results of phase III monotherapy trials of both dabrafenib and tra-metinib presented at ASCO 2012, two studies testing the combination of the BRAF and MEK in-hibitors demonstrated better patient outcomes compared to a BRAF in-hibitor alone. The com-bination has already shown promising results and lower skin toxicities compared with a BRAF

inhibitor alone in a phase II trial. An-other phase III trial (BRIM-7) is testing the already approved vemurafenib (Zel-boraf) in combination with another MEK inhibitor, GDC-0973.

“I anticipate that the combination of a BRAF inhibitor plus MEK inhibitor will become the new standard in BRAF-mu-tant melanoma in the near future,” said Ribas.

Immunotherapies are also being ac-tively explored for melanoma. Ipilim-umab (Yervoy), an anti-CTLA4 antibody, was approved in 2011 for treatment of metastatic melanoma. Two phase III tri-als are currently addressing whether ipilimumab as an adjuvant therapy for stage 3 melanoma will benefit patients.

Other novel immunotherapies in late-stage trials include the anti-PD-1 anti-bodies nivolumab and MK3475, as well as allovectin-7, MAGE-A3, and T-VEC. Results of the allovectin-7, T-VEC, and MAGE-A3 trials, and an adjuvant ipilim-umab phase III trial, may be available in 2013, according to Ribas.

Merging immunotherapies with tar-geted agents is now seen as a poten-tially promising treatment option. Two phase II trials combining vemurafenib with ipilimumab, either sequentially or in combination, are currently ongo-ing. Ribas said that he would also like to see a trial that tests the combination of a BRAF inhibitor with an anti-PD-1 or anti-PD-L1 agent. Anti-PD-L1 antibod-ies are currently in early-stage trials for metastatic melanoma.

Lung Cancer“Molecular testing [for lung cancer] is here to stay,” said D. Ross Camidge, MD, PhD, associate professor in the division of Medical Oncology at the University

of Colorado School of Medicine in Den-ver.

The recognition that molecular sub-types in smaller patient populations in non-small cell lung cancer (NSCLC) are clinically important has been well dem-onstrated with both the approval of the ALK kinase inhibitor crizotinib (Xalkori) in ALK-positive disease and the results of the LUX-Lung 3 trial showing that the irreversible EGFR inhibitor afatinib is better than chemotherapy as a front-line treatment for EGFR-mutated lung cancer. “These results have solidified that these [smaller patient populations] are not just academic pursuits and will be influencing clinical practice,” said Camidge.

Afatinib has been submitted for ap-proval in Europe based on the LUX-Lung 3 trial. A filing in the United States is expected soon. Several other trials are exploring the utility of afatinib in EGFR-mutated lung cancer, including one comparing afatinib to the reversible EGFR inhibitor gefitinib (Iressa). EGFR is currently the most common mutated gene in lung cancer patients for which there is a targeted drug.

According to Camidge, EGFR testing is still not prevalent in the United States, but if afatinib is approved, testing for EGFR will become more widespread. Er-lotinib is another EGFR inhibitor used to treat lung cancer, but the drug’s indication is not restricted to use in patients with the EGFR mutation.

NSCLC with a rear-rangement in the ROS1 gene is a relatively new subtype that makes up only about 1% to 2% of patients. As with ALK-positive patients, patients with ROS1 re-arrangements are sen-sitive to crizotinib, ac-cording to a small cohort study presented at ASCO 2012.

The immunotherapy agent nivolum-ab also is being tested in NSCLC. While Camidge believes that nivolumab has shown promising results in an early-stage trial, he is disappointed by the lack of a molecular selection strategy for some of the proposed follow-on studies in lung cancer. Phase I data showed a higher response rate in squamous cell cancer than in adenocarcinoma; squa-mous cell cancer is a subtype of NSCLC in which there have been few targeted therapy breakthroughs. The study also showed that patients who had no ex-pression of PD-L1, the binding partner

of the PD-1 protein, appeared to derive little if any benefit from the therapy. However, this biomarker was not inte-grated into the phase III trials.

“The data suggest there are patients who could be identified in advance who will derive maximal and minimal benefit from this drug,” said Camidge. “Given that the side effects are not in-significant, it is hard to see why the hy-pothesis relating to PD-L1 expression isn’t being formally tested in this study upfront.”

Overall, lung cancer diagnosis and treatment is moving toward better mo-lecular subtyping of the disease, which will help to identify and develop tar-geted agents. “I am expecting molecular characterization to be widespread in the community because the patients are go-ing to demand it,” said Camidge. TTN

D. Ross Camidge, MD, PhD

Antoni Ribas, MD, PhD

“I anticipate that the combination of a BRAF inhibitor plus MEK inhibitor will become the new standard in BRAF-mutant melanoma in the near future.”

—Antoni Ribas, MD, PhD

E N G I N E E R I N G

T H E N E X T

G E N E R A T I O N O F

A N T I B O D Y - D R U G

C O N J U G A T E S

3651_sgncor_fa5_adc_ttn.indd 2 5/16/12 2:56 PM

LinkerAttaches the cytotoxic agent to the antibody. Newer linkersystems are designed to be

stable in circulation andrelease the cytotoxic agent

inside targeted cells.4,8,9

Cytotoxic agentDesigned to kill target cells wheninternalized and released.4,8

AntibodySpecific for a tumor-associatedantigen that has restricted expression on normal cells.4,8

Attaches the cytotoxic agent to the antibody. Newer linkersystems are designed to be

stable in circulation andrelease the cytotoxic agent

inside targeted cells.

Designed to kill target cells when

Specific for a tumor-associated

4,8

Leadership in antibody-drug conjugate development

www.seattlegenetics.com

Leadership in antibody-drug conjugate developmentAntibody-drug conjugates (ADCs) use a conditionally stable linker to combine the specificity of monoclonal antibodies with the power of cytotoxic agents.1,2 This could allow drugs to be delivered directly to targeted cells and limit systemic toxicity.

Optimizing the parameters for clinical successScientists at Seattle Genetics are focused on parameters critical to the effective performance of ADCs, including target antigen selection,3,4 linker stability5-7 and potent cytotoxic agents.4,7,8

Elements of an antibody-drug conjugate

REFERENCES: 1. Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies.Bioconjug Chem. 2010;21(1):5-13. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23(9):1137-1146. 3. Carter P, Smith L, Ryan M. Identification and validationof cell surface antigens for antibody targeting in oncology. Endocr Relat Cancer. 2004;11(4):659-687. 4. Carter PJ,Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. 5. Alley SC, Benjamin DR, Jeffrey SC, et al. Contribution of linker stability to the activities of anticancer immunoconjugates. Bioconjug Chem. 2008;19(3):759-765. 6. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41(1):98-107. 7. Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: targeted drug delivery for cancer. Curr Opin Chem Biol. 2010;14(4):529-537. 8. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. 9. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358-2364. 10. Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778-784.

Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc.© 2012 Seattle Genetics, Inc., Bothell, WA 98021All rights reserved. Printed in USA US/ADC/2012/0008

ADCs link precision and potency for greater activityA preclinical (in vivo) study demonstratedthat the ADC is more active than the antibody alone (mAb) or the admixture (mAb + cytotoxic agent unlinked)10

The future of drug treatment in cancer Seattle Genetics is dedicated to improving the lives of people with cancer by developing innovative therapies for hematologic malignancies and solid tumors. For more information about Seattle Genetics and ADC technology, visit seattlegenetics.com.

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2012 in ReviewSelected Targeted Oncology Drugs Approved by the FDA

Agent (Brand Name) Description Tumor Type Indication Company Clinical Trial Leading to Approval

Approval Date

Axitinib (Inlyta)

Oral kinase inhibitor Renal cell cancer Late-stage disease after failure of 1 prior systemic therapy

Pfizer AXIS—randomized, open-label, 723-patient, phase III trial of axitinib vs sorafenib

Jan. 27, 2012

Vismodegib (Erivedge)

Oral Hedgehog pathway inhibitor

Basal cell carcinoma

Locally advanced or metastatic disease

Genentech/Roche Pharmaceuticals

ERIVANCE BCC—international, single-arm, open-label 104-patient, phase II trial

Jan. 30, 2012

Pertuzumab (Perjeta)

Recombinant, humanized antibody targeting extracellular dimerization domain of HER2

Breast cancer In combination with trastuzumab and docetaxel for previously untreated HER2-positive metastatic disease

Genentech/Roche Pharmaceuticals

CLEOPATRA—international, randomized, 808-patient, phase III trial of docetaxel plus trastuzumab vs docetaxel, trastuzumab, and pertuzumab

June 8, 2012

Cetuximab (Erbitux)

Chimeric, monoclonal, anti-EGFR antibody

Colorectal cancer First-line treatment for KRAS mutation-negative, EGFR-positive metastatic disease in combination with FOLFIRI

Bristol-Myers Squibb and Eli Lilly

CRYSTAL—international, randomized, 1217-patient, phase III trial of chemotherapy alone vs chemotherapy plus cetuximab

July 6, 2012

Carfilzomib for injection (Kyprolis)

Oral proteasome inhibitor

Multiple myeloma

Advanced disease after treatment with at least 2 therapies, including bortezomib and an immunomodulatory agent

Onyx Pharmaceuticals

PX-171-003A1—single-arm, multicenter, 266-patient, phase IIb trial;accelerated approval

July 20, 2012

Everolimus (Afinitor)

Oral mTOR inhibitor Breast cancer Advanced disease in postmenopausal women with ER+, HER2-negative disease in combination with exemestane following prior letrozole or anastrozole treatment

Novartis Pharmaceuticals

BOLERO-2—international, randomized, 724-patient, phase III trial of everolimus vs placebo in conjunction with exemestane

July 20, 2012

ziv-aflibercept injection (Zaltrap)

Angiogenesis inhibitor, binds VEGF-A, VEGF-B, and PlGF

Colorectal cancer Metastatic disease resistant to/ progressed on oxaliplatin-based chemotherapy, in combination with FOLFIRI chemotherapy

sanofi-aventis, Regeneron Pharmaceuticals

VELOUR—international, randomized, 1226-patient, phase III trial of ziv-aflibercept vs placebo plus FOLFIRI as second-line therapy

Aug. 3, 2012

Enzalutamide (Xtandi)

Oral androgen receptor antagonist

Prostate cancer Late-stage, metastatic CRPC after docetaxel therapy

Medivation, Astellas Pharma

AFFIRM—international, randomized, 1199-patient, phase III trial of enzalutamide vs placebo

Aug. 31, 2012

Bosutinib(Bosulif)

Oral Src/Abl TKI Chronic myelogenous leukemia

Chronic-, accelerated-, or blast-phase Ph+ CML resistant/intolerant to other therapies including imatinib

Pfizer Single-arm, open-label, multicenter, 546-patient trial

Sept. 4, 2012

Regorafenib (Stivarga)

Oral angiogenic, stromal, and oncogenic receptor TKI

Colorectal cancer Late-stage, metastatic disease previously treated with chemotherapy, anti-VEGF therapy, or anti-EGFR therapy

Bayer HealthCare, Onyx Pharmaceuticals

CORRECT—randomized, international, 760-patient, phase III trial of regorafenib vs placebo

Sept. 27, 2012

Cabozantinib (Cometriq)

Oral multiple TKI; inhibits RET, MET, and VEGF receptor 2

Metastatic medullary thyroid cancer

Progressive disease Exelixis Inc. EXAM—international, randomized, 330-patient phase III trial of cabozantinib vs placebo

Nov. 29, 2012

Abiraterone acetate (Zytiga)

Oral androgen biosynthesis inhibitor

Prostate cancer Metastatic CRPC in combination with prednisone in patients with no prior treatment for metastatic disease

Janssen Biotech Inc.

COU-AA-302—international, randomized, 1088-patient, phase III trial of abiraterone acetate plus prednisone or placebo plus prednisone

Dec. 10, 2012

Ponatinib (Iclusig)

Oral BCR-Abl TKI Chronic myeloid leukemia and Ph+ ALL

Advanced disease resistant/intolerant to other TKIs

Ariad Pharmaceuticals

PACE—international, 449-patient, single-arm, phase II trial; accelerated approval

Dec. 14, 2012

ALL = acute lymphoblastic leukemia; CML = chronic myelogenous leukemia; CRPC = castration-resistant prostate cancer; Ph+ = Philadelphia-chromosome-positive; PlGF = placental growth factor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor.

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Tumor Type Study Drug Description Indication Trial Trial Design Company

Breast Trastuzumab emtansine (T-DM1)

Trastuzumab linked to DM1 chemotherapy (antibody-drug conjugate)

HER2+, previously untreated/ recurrent metastatic disease

MARIANNE—1095-patient trial; ClinicalTrials.gov Identifier:NCT01120184

3-arm trial: 1) T-DM1 + pertuzumab; 2) T-DM1 + placebo; 3) trastuzumab + taxane

Roche/Genentech

Bevacizumab Anti-VEGF humanized monoclonal antibody

Adjuvant therapy for resected node-positive or high-risk, node-negative, HER2+ disease

BETH—3509-patient trial; ClinicalTrials.gov Identifier:NCT00625898

2-arm trial: 1) chemotherapy + trastuzumab; 2) chemotherapy + trastuzumab + bevacizumab

Roche/Genentech

Everolimus (Afinitor) Oral mTOR inhibitor Locally advanced or metastatic HER2+ disease

BOLERO-1—717-patient trial; ClinicalTrials.gov Identifier:NCT00876395

2-arm trial: 1) everolimus + paclitaxel + trastuzumab; 2) placebo + paclitaxel + trastuzumab


Everolimus (Afinitor) Oral mTOR inhibitor Locally advanced or metastatic HER2+ disease

BOLERO-3—569-patient trial; ClinicalTrials.gov Identifier:NCT01007942

2-arm trial: 1) everolimus + vinorelbine + trastuzumab; 2) placebo + vinorelbine + trastuzumab


Afatinib Oral TKI against HER2 and EGFR

Metastatic HER2+ disease after 1 prior trastuzumab treatment

LUX-Breast 1—780-patient trial; ClinicalTrials.gov Identifier:NCT01125566

2-arm trial: 1) trastuzumab + vinorelbine; 2) afatinib + vinorelbine

Boehringer Ingelheim Pharmaceuticals

Prostate OGX-011/ Custirsen Antisense IV drug targeting clusterin, protein overproduced in several cancer types

mCRPC SYNERGY—1000-patient trial; ClinicalTrials.gov Identifier:NCT01188187

2-arm trial: 1) custirsen + docetaxel + prednisone; 2) docetaxel + prednisone

Teva Pharmaceutical, OncoGenex Technologies

Tasquinimod Oral quinoline-3-carboxamide derivative with immunomodulatory, antiangiogenic, and antimetastatic activity

Previously untreated mCRPC

1200-patient trial; ClinicalTrials.gov Identifier: NCT01234311

2-arm trial: 1) tasquinimod; 2) placebo

Active Biotech AB

Cabozantinib (XL-184)

Prostate cancer mCRPC previously treated with docetaxel and abiraterone or MDV3100

COMET-1—960-patient trial; ClinicalTrials.gov Identifier: NCT01605227

2-arm trial: 1) cabozantinib; 2) prednisone

Exelixis

Orteronel/TAK-700

Oral nonsteroidal androgen synthesis inhibitor that selectively inhibits the enzyme CYP17A1

High-risk for disease recurrence

RTOG- and NCI-sponsored 900-patient trial; ClinicalTrials.gov Identifier: NCT01546987

2-arm trial: 1) LHRH agonist + oral antiandrogen; 2) LHRH agonist + oral antiandrogen + TAK-700

Takeda Pharmaceutical Company, Millennium Pharmaceuticals

Orteronel/TAK-700

Oral nonsteroidal androgen synthesis inhibitor that selectively inhibits the enzyme CYP17A1

mCRPC progressed following docetaxel


2-arm trial: 1) TAK-700 + prednisone; 2) placebo + prednisone

Takeda Pharmaceutical Company, Millennium Pharmaceuticals

Dasatinib (Sprycel) Oral multi- BCR/Abl and Src TKI

CRPC READY—1500-patient trial; ClinicalTrials.gov Identifier: NCT00744497

2-arm trial: 1) docetaxel + prednisone + dasatinib; 2) docetaxel + prednisone

Bristol-Myers Squibb

Melanoma Allovectin-7 Injectable plasmid-lipid complex encoding 2 microglobulin to boost immune system

Stage III/ IV metastatic melanoma with at least 1 injectable tumor


2-arm trial: 1) Allovectin-7; 2) dacarbazine or temozolomide

Vical

T-VEC (talimogene laherparepvec)

Oncolytic, recombinant virus encoding GM-CSF as potential immunotherapy vaccine

Stage III/ IV metastatic melanoma with at least 1 injectable tumor

OPTiM—439-patient trial; ClinicalTrials.gov Identifier: NCT00769704

2-arm trial: 1) T-VEC; 2) GM-CSF

BioVex Limited, Amgen


Selected Targeted Oncology Drug Pipeline, 2013: Solid-Tumor Phase III Trials

Feature


36



Dabrafenib; trametinib

Oral BRAF inhibitor; oral MEK inhibitor

Stage III/IV metastatic, previously untreated BRAFV600E/K-mutation-positive melanoma

COMBI-v—694-patient trial; ClinicalTrials.gov Identifier: NCT01597908

2-arm trial: 1) dabrafenib + trametinib; 2) vemurafenib

GlaxoSmithKline

Dabrafenib; trametinib


Stage III/IV metastatic, previously untreated BRAFV600E/K-mutation-positive melanoma

COMBI-D—340-patient trial; ClinicalTrials.gov Identifier: NCT01584648

2 arm trial: 1) dabrafenib + trametinib; 2) dabrafenib

GlaxoSmithKline

Vemurafenib/ GDC-0973 combination


Stage III, IV metastatic, previously untreated BRAFV600-

mutation-positive melanoma

BRAF-MEK inhibitor combination; 500-patient trial; ClinicalTrials.gov Identifier: NCT01689519

2-arm trial: 1) vemurafenib + GDC-0973; 2) vemurafenib

Roche Pharmaceuticals

Nivolumab (BMS-936558)

Anti-PD-1 human monoclonal antibody (IV)

Stage III, IV metastatic melanoma progressed following CTLA-4 therapy


2-arm trial: 1) nivolumab; 2) physician’s choice chemotherapy


Ipilimumab (Yervoy) Anti-CTLA4 human monoclonal antibody (IV)

Adjuvant therapy for high-risk stage III melanoma


2-arm trial: 1) ipilimumab; 2) placebo



Adjuvant therapy for high-risk stage III melanoma or stage IV metastatic melanoma, excluding all but lung metastases

NCI-sponsored 1000-patient trial; ClinicalTrials.gov Identifier: NCT01274338

2-arm trial: 1) ipilimumab; 2) high-dose recombinant interferon alfa-2b IV


MAGE-A3 (GSK 2132231A)

Multi-peptide vaccine plus adjuvant, an antigen-specific cancer immunotherapeutic

Stage III resected melanoma

DERMA—1349-patient trial; ClinicalTrials.gov Identifier: NCT00796445

2-arm trial: 1) MAGE-A3 injection; 2) placebo

GlaxoSmithKline

Lung Ipilimumab (Yervoy)

Anti-CTLA4 human monoclonal antibody (IV)

Extensive-disease SCLC

912-patient trial; CinicalTrials.gov Identifier: NCT01450761

2 arm trial: 1) ipilimumab + etoposide + cisplatin; 2) placebo + etoposide + cisplatin



Stage IV or recurrent squamous cell NSCLC


2-arm trial: 1) ipilimumab + paclitaxel + carboplatin; 2) placebo + paclitaxel + carboplatin


Nivolumab Anti-PD-1 human monoclonal antibody (IV)

Squamous cell NSCLC after failure of prior platinum-based chemotherapy


2-arm trial: 1) nivolumab; 2) docetaxel


Nivolumab Anti-PD-1 human monoclonal antibody (IV)

Nonsquamous cell NSCLC after failure of prior platinum-based chemotherapy


2-arm trial: 1) nivolumab; 2) docetaxel


Afatinib Oral TKI against HER2 and EGFR

Previously untreated stage IIIB/IV adenocarcinoma (NSCLC) of the lung with EGFR- activating mutation

LUX-Lung 6—364-patient trial; ClinicalTrials.gov Identifier: NCT01121393

2-arm trial: 1) afatinib; 2) gemcitabine + cisplatin

Boehringer Ingelheim Pharmaceuticals

CRPC = castration-resistant prostate cancer; GM-CSF = granulocyte-macrophage colony-stimulating factor; NSCLC = non-small cell lung cancer; mCRPC = metastatic CRPC; NCI = National Cancer Institute; RTOG = Radiation Therapy Oncology Group; SCLC = small-cell lung cancer; TKI = tyrosine kinase inhibitor.

Feature


37


Multiple Myeloma

Elotuzumab Humanized, monoclonal anti-CS1 antibody

Relapsed/ refractory multiple myeloma

ELOQUENT-2—640-patient trial; ClinicalTrials.gov Identifier: NCT01239797

2-arm trial: 1) lenalidomide + dexamethasone + elotuzumab; 2) Lenalidomide + dexamethasone

Bristol-Myers Squibb, Abbott Biotherapeutics

Elotuzumab Humanized, monoclonal anti-CS1 antibody

Previously untreated multiple myeloma

ELOQUENT-1—750-patient trial; ClinicalTrials.gov Identifier: NCT01335399

2-arm trial: 1) lenalidomide + dexamethasone + elotuzumab; 2) lenalidomide + dexamethasone

Bristol-Myers Squibb, Abbott Biotherapeutics



Relapsed multiple myeloma

ENDEAVOR—888-patient trial; ClinicalTrials.gov Identifier: NCT01568866

2-arm trial: 1) carfilzomib + dexamethasone; 2) bortezomib + dexamethasone




Relapsed multiple myeloma


2-arm trial: 1) lenalidomide + dexamethasone + carfilzomib; 2) lenalidomide + dexamethasone


Perifosine/KRX-0401

Oral mitogen-activated protein kinase (MAPK) pathway inhibitor with pro-apoptotic activity

Multiple myeloma relapsed on bortezomib therapy


2-arm trial: 1) perifosine + bortezomib + dexamethasone; 2) bortezomib + dexamethasone

AEterna Zentaris, Dana-Farber Cancer Institute

Leukemia Midostaurin Oral multi-target protein kinase inhibitor

Newly diagnosed acute myeloid leukemia

RATIFY—NCI- and CALGB-sponsored 714-patient trial; ClinicalTrials.gov Identifier: NCT00651261

2-arm trial: 1) midostaurin + cytarabine + daunorubicin; 2) cytarabine + daunorubicin + placebo


Obinutuzumab Humanized, glycoengineered, monoclonal anti-CD20 antibody

Previously untreated chronic lymphocytic leukemia

CLL11—786 patient trial; ClinicalTrials.gov Identifier: NCT01010061

3-arm trial: 1) obinutuzumab; 2) rituximab; 3) chlorambucil

Roche Pharmaceuticals, Genentech, German CLL Study Group

Ibrutinib Oral Bruton’s tyrosine kinase inhibitor

Relapsed/refractory chronic lymphocytic leukemia

RESONATE—350-patient trial; ClinicalTrials.gov Identifier: NCT01578707

2-arm trial: 1) ofatumumab; 2) ibrutinib

Pharmacyclics, Janssen Research & Development, LLC

Lymphoma Brentuximab vedotin (Adcetris)

Antibody drug conjugate of brentuximab anti-CD30 antibody

High risk of residual Hodgkin lymphoma after stem cell transplant

AETHERA—329-patient trial; ClinicalTrials.gov Identifier: NCT01100502

2-arm trial: 1) brentuximab vedotin; 2) placebo

Seattle Genetics, Inc, Millennium Pharmaceuticals

Ibrutinib Oral Bruton’s tyrosine kinase inhibitor

Relapsed/ refractory mantle cell lymphoma


2-arm trial: 1) ibrutinib;2) temsirolimus

Janssen Research & Development, LLC, Pharmacyclics

Obinutuzumab Humanized, glycoengineered, monoclonal anti-CD20 antibody

Untreated, advanced indolent non-Hodgkin lymphoma

GALLIUM—1400-patient trial; ClinicalTrials.gov Identifier: NCT01332968

2-arm trial: 1) obinutuzumab; 2) rituximab

Roche Pharmaceuticals, GLSG, NCRI

MLN8237/Alisertib

Oral Aurora A kinase inhibitor

Relapsed/ refractory peripheral T-cell lymphoma

354 patient trial; ClinicalTrials.gov Identifier: NCT01482962

2-arm trial: 1) alisertib; 2) investigator’s choice single agent

Millennium Pharmaceuticals

Panobinostat Histone deacetylase (HDAC) inhibitor

Maintenance therapy after autologous stem cell transplant in Hodgkin lymphoma


2-arm trial: 1) panobinostat; 2) placebo


CALGB = Cancer And Leukemia Group B; GLSC = German Low-Grade Lymphoma Study Group; NCI = National Cancer Institute; NCRI = UK National Cancer Research Institute.

Selected Targeted Oncology Drug Pipeline, 2013: Hematologic Malignancy Phase III Trials

Research Profile


38

For the past 10 years, Matthew J.C. Ellis, MB BChir, PhD, has focused his research on exploring the breast cancer genome in partnerships with academic and government-funded centers in the United States and the United King-dom.

Ellis, the Anheuser-Busch chair in Medical Oncol-ogy at Washington University School of Medicine in St. Louis, Missouri, served as co-leader of a groundbreak-ing analysis of breast cancer tumors that was published in Nature in September 2012. The other co-leader was Charles M. Perou, PhD, who heads the Perou Laboratory at the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill.

The study, a project of the The Cancer Genome Atlas (TCGA), confirmed the existence of four major subtypes of breast cancer through the most comprehensive anal-ysis to date of genetic mutations in breast tumors.Ellis talked about his research in an interview.

What was the biggest surprise when you analyzed the breast cancers across the six platforms?We were quite surprised regarding the degree of simi-larity between basal-like breast cancer and high-grade serous ovarian cancer. Currently, these two diseases are treated differently. While both are treated with taxane drugs, ovarian cancer patients are typically adminis-tered a platinum-based agent because a decade or more ago, gynecologic oncologists decided that anthracyclines add little when there is a platinum agent in the regimen. Breast cancer therapy is still focused on the use of an-thracyclines such as doxorubicin. Anthracyclines cause heart damage and leukemia, and so we have long been in-terested in a replacement regimen. The TCGA data there-fore suggest that we should explore the hypothesis that a platinum-based regimen without an anthracycline may be just as effective for basal-like breast cancer, or even more effective than the standard regimens with fewer long-term side effects. Some clinicians have begun using these agents based on the reports in the literature. As of yet, however, a clinical trial using platinum-based com-pounds in place of an anthracycline-based regimen has not been conducted.

Is there a concise way to describe potentially optimal treatment regimens for the four subtypes?Each subtype exhibited some type of feature that upreg-ulated the PI3 kinase pathway. Luminal and HER2-pos-itive tumors showed a high frequency of mutation spe-cifically in the PIK3CA gene. Basal-like tumors tended to upregulate the PI3 kinase pathway by loss of negative regulators such as PTEN and INPP4B. These observa-tions suggest that targeting this pathway with various inhibitors may give us a way to shut down a common deregulated pathway in each subtype.

Will your study, do you think, change the accepted paradigms for treating the three phenotypic groups (ie, HER2-positive, ER-positive, and triple-negative)?We now recognize that different breast cancers are so dramatically distinct that their treatment needs to be reevaluated. This is especially true of hormone-positive tumors where the typical targeted therapy regimen in-cludes tamoxifen or aromatase inhibitors. If we combine inhibition of other pathways such as FGFR, PIK3CA, MDM2, and CDK4/6, we may be able to increase the ther-apeutic efficacy of endocrine therapy-based regimens.

Are there any tests, or would you like to see the development of any tests, that would further elucidate and define the subgroups?In luminal-type breast cancers, a screen against the PIK3CA mutation would be beneficial to see whether pa-tients might be receptive to inhibition of this pathway. A test for EGFR phosphorylation status in HER2-positive disease could also help clinicians distinguish the two subtypes of HER2-positive cancer, and such an approach might be beneficial in predicting the response to trastu-zumab, as well. BRCA1 and 2 mutation status could be useful to knowing which triple-negative breast cancer should be treated with PARP inhibitors.

What questions about treating breast cancer subtypes remain unanswered?There are many. Perhaps one to highlight is that one of the standards in the diagnosis of breast cancer is to as-sess the status of HER2 in the disease. Prior to this work, it was typically assumed that HER2-positive breast can-cers were homogeneous enough to warrant across-the-board trastuzumab treatment. The TCGA analysis dem-onstrates that at least two subtypes of the HER2-positive tumor exist. One overexpresses HER2 in combination with other upregulated receptor tyrosine kinases. The other possesses hormone positivity in addition to am-plified HER2. This second group appears to express less HER2 with a reduction in signaling, implying that the disease is less addicted to HER2 signaling. This could help to explain why only half of patients with HER2-pos-itive disease respond to trastuzumab therapy. TTN

Exploring the Breast Cancer Genome

Matthew J.C. Ellis, MB BChir, PhDProfessor, Department of MedicineDirector, Section of Breast OncologyCo-Director, Clinical and Transla-tional Research, Siteman Compre-hensive Cancer Center Washington University, School of MedicineSt. Louis, MO

* Stratifi ed by histology (adenocarcinoma vs non-adenocarcinoma), race (Asian vs non-Asian and Indian subcontinent), ECOG performance status score (0-to-1 vs 2), smoking status (never-smoker vs ever smoker).

NSCLC = non-small cell lung cancer; ECOG = Eastern Cooperative Oncology Group.

Reference: 1. Data on fi le. Pfi zer Inc, New York, NY.

This information is current as of October 2011.

Dacomitinib (PF-00299804) is an investigational compound

Enrolling inAdvanced NSCLCInvestigating dacomitinib, an irreversible

pan-HER inhibitor, versus erlotinib in second- or third-line therapy for advanced NSCLC1

Phase 3, randomized, double blind, multinational, multicenter study in NSCLC patients after at least one prior course of chemotherapy

Coprimary populations: all enrolled NSCLC patients and NSCLC patients confi rmed for KRAS wild type

End PointsPrimary: Progression-free survival

Secondary: Overall survival, objective response rate, duration of response, safety and tolerability, and patient-reported outcomes

For more information, please contact the Pfi zer Oncology Clinical Trial Information Service at:

1-877-369-9753 in the United States and Canada (toll-free)

+1-646-277-4066 outside the United States

For more information, please visit www.pfi zercancertrials.com or www.clinicaltrials.gov (NCT01360554)

Patients with locally advanced or metastatic NSCLC following progression after, or intolerance to, at least one prior course of chemotherapy

N = 800

1:1

RANDOMIZATIO

N*

Dacomitinib 45 mg orally once daily

Erlotinib150 mg orally once daily

PFW 00029-B © 2012 Pfi zer Inc. All rights reserved.

* Stratifi ed by histology (adenocarcinoma vs non-adenocarcinoma), race (Asian vs non-Asian and Indian subcontinent), ECOG performance status score (0-to-1 vs 2), smoking status (never-smoker vs ever smoker).

NSCLC = non-small cell lung cancer; ECOG = Eastern Cooperative Oncology Group.

Reference: 1. Data on fi le. Pfi zer Inc, New York, NY.

This information is current as of October 2011.

Dacomitinib (PF-00299804) is an investigational compound

Enrolling inAdvanced NSCLCInvestigating dacomitinib, an irreversible

pan-HER inhibitor, versus erlotinib in second- or third-line therapy for advanced NSCLC1

Phase 3, randomized, double blind, multinational, multicenter study in NSCLC patients after at least one prior course of chemotherapy

Coprimary populations: all enrolled NSCLC patients and NSCLC patients confi rmed for KRAS wild type

End PointsPrimary: Progression-free survival

Secondary: Overall survival, objective response rate, duration of response, safety and tolerability, and patient-reported outcomes

For more information, please contact the Pfi zer Oncology Clinical Trial Information Service at:

1-877-369-9753 in the United States and Canada (toll-free)

+1-646-277-4066 outside the United States

For more information, please visit www.pfi zercancertrials.com or www.clinicaltrials.gov (NCT01360554)

Patients with locally advanced or metastatic NSCLC following progression after, or intolerance to, at least one prior course of chemotherapy

N = 800

1:1

RANDOMIZATIO

N*

Dacomitinib 45 mg orally once daily

Erlotinib150 mg orally once daily

PFW 00029-B © 2012 Pfi zer Inc. All rights reserved.

Evidence-Based Oncology


40

Precision Medicine and the Rapidly Approaching Future of Cancer ManagementMaurie Markman, MD

to interpret the clinical implications of the findings, or how to use the infor-mation to develop the most effective therapeutic strategy.

Another possible way to highlight this critically important distinction is to compare obtaining the sequenc-ing data itself (as truly eloquent as this may be) with the simple discov-ery of a previously hidden treasure

map or a secret code. And, as interest-ing as such events may be, it is only after the map/code has been correctly interpreted and the treasure found or the code broken that the map/code is of genuine value to its owner(s), just as the successful interrogation of the highly complex genomic data and the discovery of clinical relevance will be required before one can conclude there is true value to the patient associated with this effort.

The Multiple Unanswered QuestionsHow long it will take to discover the clinical relevance of these molecular data in particular clinical settings (eg, triple-negative breast cancer, squa-mous cell lung cancer) or in individual patients in such settings (eg, PI3 kinase mutation in ovarian cancer) and to develop effective therapeutics based on the abnormalities identified remains a critical unknown.

It is clear that it will be increasingly possible to obtain molecular profiles on individual tumors in a highly cost-effective manner. Further, with time the essential informatics support

mechanism of resistance to such inhi-bition compared with treatment with the BRAF inhibitor alone.9

So, within a remarkably limited period of time we have gone from a theorized role for the presence of a BRAF mutation in the progression of malignant melanoma,10 to the demon-stration of the favorable impact asso-ciated with administering an inhibi-tor directed at that mutation,7 to a strategy that effectively (at least for a clinically meaningful period of time) interferes with a cancer’s ability to resist the effects of such inhibition of its growth.9

The Impact of the Revolution in Genomic Sequencing TechnologyPerhaps the single most important fac-tor in propelling this spectacular new era forward has been the stunning advances in the technology associated with sequencing.11,12 The combined activities of industry and academia have led to a profound reduction in both the time required and costs asso-ciated with generating these vitally important data.

Consider the fact that the land-mark report of the first completely sequenced human genome less than two decades ago required a number of years to accomplish at a cost of several billion dollars. It is estimated that this process can currently be accomplished in a matter of days at a cost of several thousand dollars.12 And both the time required and cost of conducting the sequencing for individual tumor speci-mens (and corresponding nonmalig-nant tissue in the same individual) will almost certainly decrease in the future.

Viewing the Map Versus Breaking the Code for Individual CancersIt is essential to acknowledge the fun-damental difference between possess-ing specific sequencing data on indi-vidual tumors, or even highly detailed knowledge of the differences present within such tumors, compared with the corresponding genome of the non-malignant tissue in that individual patient versus actually knowing how

receptors in breast cancers to deter-mine if hormonal manipulation (eg, removal of the ovaries, administration of tamoxifen) is an appropriate man-agement strategy for that specific indi-vidual.

However, what has changed over the past 10+ years is the number of unique settings where such data are of clini-cal relevance and the rather remark-able acceleration in the development of such knowledge in additional malig-nancies.

Consider for a moment the fact that it was less than two years ago when the first solid reports appeared identifying the fact that a class of antineoplastic agents known as BRAF inhibitors could produce rather spectacular responses in patients with metastatic mela-noma whose cancers possessed par-ticular mutations in BRAF.7 However, despite this very short time interval, a recently reported phase III trial has

now revealed the clinical superiority (prolongation of time-to-disease pro-gression) associated with combining a BRAF inhibitor with another “targeted” agent shown to influence a common

It is difficult to overstate how much our ability to study the fundamental molecular profiles within individual

tumors has revolutionized our basic understanding of the biology of malig-nant disease.1-3 Further, this informa-tion has clearly identified both the het-erogeneity of possible driver mutations and pathways within the cancers of individual patients, as well as the large number of possible resistance mecha-nisms available to permit individual cancers to overcome both traditional cytotoxic and the more “targeted” anti-neoplastic agents.4

However, as interesting as this infor-mation may be to cancer biologists, what is far more relevant to cancer patients, their families, and treat-ing oncologists is how such data can be increasingly utilized to favorably impact clinical outcomes.5-7

Precision MedicineThe term precision medicine has been used to describe the impact of knowl-edge of the unique molecular changes present in individual tumors to devise a more precise therapeutic strategy for that particular patient.8 The “pre-cision” will hopefully result in both improved efficacy (greater “on-target” effect) and reduced toxicity (less “off-target” effect).

It is relevant to acknowledge here that this process of precision medicine is certainly not a new concept. For exam-ple, for more than 40 years physicians have used knowledge of the presence (or absence) of estrogen/progesterone

The term precision medicine has been

used to describe the impact of

knowledge of the unique molecular

changes present in individual tumors

to devise a more precise therapeutic

strategy for that particular patient.

It is clear that it will be increasingly

possible to obtain molecular profiles

on individual tumors in a highly

cost-effective manner.

Maurie Markman, MD

Targeted Therapy

duced an outcome of genuine clinical value. TTN

References1. DeVita VT Jr, Rosenberg SA. Two hundred years

of cancer research. N Engl J Med. 2012;366(23):

2207-2214.

2. Patel JP, Gonen M, Figueroa ME, et al. Prog-

nostic relevance of integrated genetic profiling in

acute myeloid leukemia. N Engl J Med. 2012;366

(12):1079-1089.

3. McDermott U, Downing JR, Stratton MR.

Genomics and the continuum of cancer care. N Engl J Med. 2011;364(4):340-350.

4. Gerlinger M, Rowan AJ, Horswell S, et al.

Intratumor heterogeneity and branched evolu-

tion revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-892.

5. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy

and safety of a specific inhibitor of the BCR-ABL

tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037.

6. Demetri GD, von Mehren M, Blanke CD, et

al. Efficacy and safety of imatinib mesylate in

advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472-480.

7. Sosman JA, Kim KB, Schuchter L, et al. Sur-

vival in BRAF V600-Mutant advanced melanoma

treated with vemurafenib. N Engl J Med. 2012;

366(8):707-714.

8. Mirnezami R, Nicholson J, Darzi A. Preparing

for precision medicine. N Engl J Med. 2012;366

(6):489-491.

9. Flaherty KT, Infante JR, Daud A, et al. Com-

bined BRAF and MEK inhibition in melanoma with

BRAF V600 mutations. N Engl J Med. In press.

10. Davies H, Bignell GR, Cox C, et al. Muta-

tions of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954.

11. Pasche B, Absher D. Whole-genome sequenc-

ing: a step closer to personalized medicine. JAMA. 2011;305(15):1596-1597.

12. Tran B, Dancey JE, Kamel-Reid S, et al. Can-

cer genomics: technology, discovery, and trans-

lation. J Clin Oncol. 2012;30(6):647-660.

13. Markman M, Markman J, Webster K, et al.

Duration of response to second-line, platinum-

based chemotherapy for ovarian cancer: implica-

tions for patient management and clinical trial

design. J Clin Oncol. 2004;22(15):3120-3125.

14. Von Hoff DD, Stephenson JJ, Rosen P, et al.

Pilot study using molecular profiling of patient’s

tumors to find potential targets and select treat-

ments for their refractory cancers. J Clin Oncol. 2012;28(33):4877-4883.

with “Mutation X” in “Cancer Y” treated with “Drug A”) to be collected (with any information identifying the individual completely removed) in a database to be joined with such data obtained from similar patients (again, among that 1% of patients with “Mutation X” in “Cancer Y” treated with “Drug A”) to evaluate the efficacy (or perhaps even unique toxicity) associated with the use of this specific agent in the par-ticular setting.

By combining a number of “N of 1” experiences, it should be possible to obtain a reasonable view of the relative or absolute benefits associated with the use of this agent. Depending on the

particular setting, the relevant end-point could be the objective response rate or progression-free survival (com-pared with a recognized historical population) in the first 20 or 30 “N of 1” patient experiences.

An additional and quite novel end-point to consider would be to use the patient as her/his own control, with the time to disease progression on the current regimen (selected at least in part based on molecular testing) being compared with the time to disease progression on the individual patient’s prior treatment regimen.

Based on a rational view of biological systems, there is no reason to believe that the rate of disease progression in an individual tumor should improve/

Future advances in antineoplastic

drug therapy will be increasingly

based on knowledge of the relevant

driver mutations/pathways in

individual cancers.

Feature


41

will surely be able to analyze/inter-pret possible clinical implications of unique findings. However, a number of highly relevant questions will need to be addressed to permit the most effec-tive use of this spectacular new tech-nology.

For example, if a molecular abnor-mality is identified in an individual patient’s cancer that has been associ-ated with the favorable effect of a par-ticular commercially available antineo-plastic agent but in a different tumor type, is it essential for a clinical trial to be conducted and the results reported before it is possible for patients to be treated with that agent in the new tumor site?

Should third-party payers be encour-aged, or perhaps even required to pay for such treatment based on the pres-ence of a very specific molecular profile that identifies a potential driver muta-tion in a tumor where formal regula-tory approval for this indication has not occurred? Now add to this query the fact that only a very small percent-age of patients with this particular tumor type will possess the abnormal-ity (eg, <2% to 5%), making it very diffi-cult (if not truly impossible) to conduct a comparative phase III or even a non-randomized phase II study.

In fact, it is highly likely that the scenario posed above will be very com-mon once whole-genome sequencing becomes rather standard in the man-agement of advanced or recurrent can-cers. How should the 1% of patients found to have “Mutation X” in “Cancer Y” be managed if the documented pres-ence of “Mutation X” in “Cancer Z” has been shown to be favorably impacted if “Drug A” (FDA–approved for “Cancer Z”) is administered?

A Novel Clinical Cancer Research Paradigm: “N of 1”In the opinion of this commentator, the outline of a possible solution to this complex individual patient and societal dilemma can be provided by proposing a paradigm-changing clini-cal research strategy, called by some “N of 1.”

This strategy requires the outcome data generated following the patient described above (eg, 1% of patients

decrease over time in the absence of a favorable effect of a biologically and clinically active antineoplastic pro-gram. Thus, if the time to disease pro-gression is longer following the cur-rent regimen, compared with the prior regimen, it is reasonable to conclude this outcome must have been due (at least in part) to the effects of the cur-rent treatment.13 This novel approach to evaluating efficacy of molecularly based anti-neoplastic therapy has been employed in at least one previously reported highly provocative clinical trial.14

Further, the value of the “N of 1” strat-egy may be substantially enhanced by a proposal that the overall result of a particular experience will be declared to be “positive” only if a genuinely major favorable outcome is docu-mented.

Thus, in this research scenario, a 10% to 15% objective response rate with responses lasting a median of 2 to 3 months will unlikely be considered an outcome that would justify “fur-ther research,” as is often stated in the conclusions of manuscripts describing the results of phase II drug trials in the cancer arena. Rather, in this concept, considering both the likely toxicity and anticipated costs of these treatment strategies, one will be looking for solid evidence of more meaningful clini-cal activity (eg, minimum 30% to 40% objective response rate persisting a median of >5 to 6 months).

ConclusionFuture advances in antineoplastic drug therapy will be increasingly based on knowledge of the relevant driver muta-tions/pathways in individual cancers. Technological advances will soon make it possible to rapidly, cost-effectively, and routinely examine the molecular profiles of the tumors in individual cancer patients.

However, a new clinical research par-adigm will be required to evaluate the effectiveness of therapy when small subsets of patients are being managed with a novel strategy. Finally, serious and unavoidable cost considerations will soon mandate a far higher thresh-old for a new/novel antineoplastic strategy to be considered to have pro-

™

Visit LetsTestNow.com Expert commentary Relevant case studies Insights about your role in biomarker testing The benefits of a multidisciplinary approach

References: 1. Riely GJ. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. J Thorac Oncol. 2008;3(suppl 2):S146-S149. 2. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380. 3. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967. 4. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703. 5. Data on file. Synovate US Oncology Monitor (USTOM), Jan-Dec 2011. 6. National Cancer Institute. Lung cancer. Non-Small Cell Lung Cancer Treatment (PDQ). Cellular classification of NSCLC. http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional/page2. Accessed January 18, 2012.

You play a critical role as part of the multidisciplinary team that identifies biomarkers to diagnose and treat advanced NSCLC

~1 in 5 patients with advanced NSCLC has a tumor with EGFR (ErbB1) mutations or ALK rearrangements1-6

You can help improve patient outcomes through a multidisciplinary approach

Copyright ©2012. Boehringer Ingelheim Pharmaceuticals, Inc.All rights reserved. (5/12) OC209900PROF-A

With biomarker testing in advanced non–small-cell lung cancer (NSCLC)...

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25C

, 16M

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