Welcome!Please take a moment to complete the short

pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities.

Faculty Disclosures

The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:• Presenter, MD: Research: Pharma Company; Consultant:

Pharma CompanyTO BE FILLED IN BY

PRESENTING PHYSICIAN(S)Off-label discussion disclosure: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Steering Committee Disclosures

The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:• Debu Tripathy, MD: Consultant: Clovis Oncology; Clinical Investigator:

Piramal Pharmaceuticals

• Kathy Miller, MD: Speaker/Consultant: Genentech/Roche; Consultant: AstraZeneca, Bristol-Myers Squibb

Non-faculty Disclosures

Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:

Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz: Nothing to Disclose

Michelle Melisko, MD: Speaker: Agendia,Genentech/Roche, Novartis, Bristol-Myers Squibb. Clinical Investigator: Amgen, AstraZeneca, Celldex.

Educational Objectives

At the conclusion of this activity, participants should be able to demonstrate the ability to:

• Review the recently updated clinical practice guidelines for HER2-positive breast cancer

• Discuss recent data with HER2-targeted agents in the neoadjuvant and adjuvant settings and choose the optimal treatment for patients with early-stage HER2-positive breast cancer and patients with abnormal cytogenetics

• Assess the various treatment strategies for patients with locally advanced or metastatic HER2-positive breast cancer

• Identify eligibility criteria and the status of currently accruing clinical trials in HER2-positive breast cancer and counsel patients accordingly

Paper Audience Response Questions• During the course of the

program Audience Response Questions will be asked to determine the current knowledge of the audience

• These questions will not be graded and are for outcomes purposes only

• Please record your answers on your evaluation form located in your packet

HER2 Oncogene: A Biological Target

• Increased Aggressiveness

• Shortened Survival

• Hormonal Resistance

HER2 protein overexpression

HER2 gene amplification

HER1/EGFR

HER2 HER3

HER4

PI3K/AKTRas/MEK/MAPK

(STAT)

TFCoA

CoR

ProliferationMigrationDifferentiationApoptosis

P

EGF

TGF

AR

HRGHRG

TK

TK

TK

X

HER Family Ligands and Signaling

P

EARLY STAGE/ADJUVANT THERAPY

Adjuvant Trastuzumab Trial Designs

Summary of Trastuzumab AdjuvantTrial DFS Benefits

Study FU, yrs N

HERA1 3,387

2 3,401

NSABP B-31/NCCTG 9891

2 3,351

4 3,833

BCIRG 006 3 3,222

FinHer 3 231

PACS 04 4 528

0 1 2In favor of T In favor of Obs.

HR0.54

0.64

0.48

0.52

0.64

0.42

0.86

Dahabreh IJ, et al. The Oncologist 2008 ;13(6): 620-630

NSABP/NCCTG Update – Disease-Free Survival

Years From RandomizationPerez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.

Median F/U 3.9 years

HR=0.52, P<.001

NSABP/NCCTG Update – Overall Survival

Years From RandomizationPerez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.

Median F/U 3.9 years

HR=0.61, P<.001

BCIRG 006 Study – Final Analysis

Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX;Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.

Concurrent vs Sequential Therapy: N9831 Trial

Perez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.

HERA Trial Update – Median F/U 4 YearsDisease-Free Survival, Censored for Crossover

Gianni L, et al. Lancet Oncol. 2011;12(3):236-244.

Unadjusted HR censored for crossover = 0.69P<.0001

Trial

HERA

B31

N9831

BCIRG 006

FinHer

Arm

Control H 1 year

ACPACPH

ACP ACPH

ACPH

ACDACDH

TCH

No HH

BaselineLVEF, %

>55

>50

>50

>50

CHF, %

Cardiacdeath, n

10

10

110

000

00

Smith I, et al. Lancet. 2007;369(9555):29-36; Perez EA, et al. J Clin Oncol. 2008;26(8):1231-1238; Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.; Rastogi S, et al. Cardiovasc Drugs Ther. 2007;21(6):415-422; Rastogi S, et al. J Clin Oncol. 2007; 25 (964S; LBA513)

02.1

0.83.80.32.8 3.3

0.62.00.4

10

Clinical Cardiomyopathy FromTrastuzumab Adjuvant Trials

H = Trastuzumab; A = Doxorubicin; C = Cyclophosphamide; P = Paclitaxel; D = Docetaxel.

Any Chemo

Case

A 59-year-old postmenopausal woman undergoes a left lumpectomy and sentinel node biopsy for a 2.2-cm grade II infiltrating ductal cancer that is ER/PR+ and HER2+ (FISH ratio 3.7). Neither of 2 sentinel nodes examined contain tumor. Chest x-ray and serum chemistries including liver function test are normal. A cardiac ejection fraction by MUGA scan is normal at 56%.

What would you recommend for this patient?

A. An aromatase inhibitor (AI) for 5 years plus trastuzumab for 1 year

B. Docetaxel and cyclophosphamide for 4 cycles followed by an AI for 5 years

C. Docetaxel, carboplatin, and trastuzumab for 6 cycles with trastuzumab for 1 year and an AI for 5 years

D. Doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab, with trastuzumab for 1 year and an AI for 5 years

ARS Question 1

ARS Question 1 Response

What would you recommend for this patient?

A. An aromatase inhibitor (AI) for 5 years plus trastuzumab for 1 year

B. Docetaxel and cyclophosphamide for 4 cycles followed by an AI for 5 years

C. Docetaxel, carboplatin, and trastuzumab for 6 cycles with trastuzumab for 1 year and an AI for 5 years–Reasonable choice

D. Doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab, with trastuzumab for 1 year and an AI for 5 years

• HERA and BCIRG 006 trials enrolled patients with node-negative HER2+ breast cancer

• In the HERA study, patients had to have tumor >1cm if node-negative (one third of all patients)

• In the BCIRG 006 study, high-risk node negative cases were enrolled, defined as tumor >2 cm, or ER- and PR-negative or histologic grade 2 or 3 (29% of patients enrolled)

• Subset analysis of these trials have shown a statistically significant reduction in risk of recurrence in node-negative patients, but as expected, the absolute magnitude of risk reduction is lower compared to that of node-positive patients.

• In this case, the patient would have been eligible for either of these trials and therefore would be expected to derive a benefit from chemotherapy plus trastuzumab. Given the smaller benefit, the regimen with lower cardiac toxicity (TCH) would be preferable.

0.0 0.5 1.0 1.5HR

Europe, Canada, SA, Australia, NZ (2438) 161 vs 235 0.66 (0.54, 0.81)Asia Pacific, Japan (405) 21 vs 37 0.53 (0.31, 0.90)Eastern Europe (369) 23 vs 36 0.54 (0.32, 0.91)

Region of the world

<35 years (253) 19 vs 31 0.57 (0.32, 1.01)35-49 years (1508) 89 vs 150 0.54 (0.42, 0.70)50-59 years (1096) 71 vs 97 0.71 (0.52, 0.97)>60 years (544) 39 vs 43 0.91 (0.59, 1.41)

Premenopausal (491) 43 vs 49 0.80 (0.53, 1.21)Uncertain (1373) 70 vs 135 0.48 (0.36, 0.64)Postmenopausal (1535) 105 vs 137 0.75 (0.58, 0.97)

Neoadjuvant CT (372) 39 vs 50 0.66 (0.43, 1.00)Negative (1099) 34 vs 58 0.59 (0.39, 0.91)1-3 positive nodes (976) 50 vs 80 0.61 (0.43, 0.87)

Nodal status

Menopausal status at randomisation

Age at randomisation

No. eventsT vs obs

HR (95% CI)Subgroup (No. patients)

>4 positive nodes (953) 95 vs 132 0.64 (0.49, 0.83)

Central + South America (189) 13 vs 13 0.98 (0.45, 2.11)

All patients (3401) 218 vs 321 0.64 (0.54, 0.76)

Overall ResultSmith I, et al. Lancet. 2007;369(9555):29-36.

Exploratory DFS Subgroup Analysis (ITT):1-year Trastuzumab vs Observation – HERA Trial

BCIRG 006 Trial, Node-Negative SubsetDisease-Free Survival

Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX (Abstr 62);Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.

BCIRG 006 Trial, Node-Negative SubsetOverall Survival

Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX (Abstr 62);Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.

The patient is treated with AC → paclitaxel with trastuzumab and completes the chemotherapy portion of therapy without any problems. Trastuzumab is planned for a total trastuzumab duration of 1 year.

What would you recommend at this point?

A. Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after radiation

B. Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after trastuzumab

C. Initiation of radiation therapy to the left breast and resumption of trastuzumab and hormonal therapy after radiation

D. Initiation of radiation therapy to the left breast and resumption of trastuzumab after radiation, with hormonal therapy after trastuzumab

ARS Question 2

What would you recommend at this point?

A. Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after radiation–Reasonable choice

B. Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after trastuzumab

C. Initiation of radiation therapy to the left breast and resumption of trastuzumab and hormonal therapy after radiation

D. Initiation of radiation therapy to the left breast and resumption of trastuzumab after radiation, with hormonal therapy after trastuzumab

ARS Question 2 Response

• The NCCTG N9831 and NSABP B-31 trials were designed to allow radiation following chemotherapy as indicated by standard of care to overlap with the administration of trastuzumab

• Hormonal therapy was to be given as standard of care following chemotherapy and to overlap with the administration of trastuzumab

This patient would receive radiation as standard of care following a lumpectomy and hormonal therapy based on ER and PR positivity. Analysis of adverse events based on radiation therapy in the N9831 did not show a difference in cardiac adverse events or other adverse events.

Cardiac Adverse Events With or Without RT: N9831

HR RT vs No RT/Unknown = 0.7; P=.21

Halyard MY, et al. J Clin Oncol. 2009;27(16):2638-2644.

Three months after completion of chemotherapy as trastuzumab therapy is ongoing, a follow-up cardiac ejection fraction (EF) is found to be 45%. The patient has no cardiac symptoms and has a normal cardiac examination along with an excellent performance status.

What would you recommend?

A. Permanent discontinuation of trastuzumabB. Continuation of trastuzumab with a recheck of EF in 1 monthC. Continuation of trastuzumab with the addition of a beta blocker and

angiotensin converting enzyme inhibitor with a recheck of EF in 1 monthD. Discontinuation of trastuzumab with a recheck of EF in 1 month and

restarting trastuzumab if EF recovers to more than 50%

ARS Question 3

What would you recommend?A. Permanent discontinuation of trastuzumabB. Continuation of trastuzumab with a recheck of EF in 1

monthC. Continuation of trastuzumab with the addition of a beta

blocker and angiotensin converting enzyme inhibitor with a recheck of EF in 1 month

D. Discontinuation of trastuzumab with a recheck of EF in 1 month and restarting trastuzumab if EF recovers to more than 50%–Reasonable choice

ARS Question 3 Response

Cardiac dysfunction is seen at a rate of 3-10% and is usually subclinical, with clinical signs of congestive heart failure seen at a rate of 0.5-3.8%. Cardiac function usually recovers over time and the long-term consequences are still unknown. The guidelines for evaluating cardiac status is empiric and based on the design of most adjuvant trials. These trials required normal EF prior to initiation of trastuzumab (usually defined as EF >50%), and monitoring every 3 months. For clinical congestive heart symptoms, immediate EF evaluation is recommended to verify cardiac cause, with permanent discontinuation of trastuzumab. For asymptomatic decreases in cardiac function, guidelines are recommended (see next slide) that the trials used for holding trastuzumab and rechecking, with restarting once criteria for continuation are met.

Within Normal Limits

1-5% below LLN

6% below LLN

Cont.

Hold *

Hold *

Relationship of LVEF to LLN

Absolute Decreaseof <10%

Absolute Decrease of 10-15%

Absolute Decrease of 16%

Hold *

Hold *

Hold *

Cont.

Cont.

Cont.*

* Repeat LVEF assessment after 4 weeks - If criteria for continuation met – resume trastuzumab

- If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab

Asymptomatic PatientsRules for Trastuzumab Continuation Based on Serial LVEF Used in Trials

Romond EH, et al. N Engl J Med. 2005; 353: 1673-84; Russell S, et al. J Clin Oncol. 2010;28(21):3416-3421; Procter M, et al. J Clin Oncol. 2010;28(21):3422-3428.

METASTATIC BREAST CANCER

1.0

0.0

0.2

0.4

0.6

0.8

P<.001

0 5 10 15 20 25Months

Trast + CT (n=235) Median TTP = 7.4 mon

CT alone (n=234) Median TTP = 4.6 mon

Prob

abili

ty

Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.

Trastuzumab Increases Time to Progression in HER2(+) MBC

Trastuzumab Added to ChemoRxImproves Survival in MBC

Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.

RR=0.76P=.025

Lapatinib Increases Time to ProgressionAfter Trastuzumab

* Censors 4 patients who died due to causes other than breast cancer.

70

10

20

30405060708090

0

100

10 20 30 40 50 600Time (weeks)

CapecitabineLapatinib +

capecitabine

.00016P value (log-rank, 1-sided)

69 (43%)45 (28%)Progressed or died*19.736.9Median TTP, wk

161160No. of pts

0.51 (0.35, 0.74)Hazard ratio (95% CI)

% o

f pat

ient

s fre

e fro

m p

rogr

essi

on*

Geyer CE, et al. N Engl J Med. 2006;355(26):2733-2743.

X XH0

10

20

30

40

50

60

70

80

90

100

% o

f pts

54 (42.1-65.7)

75.3%(64.2-84.4)

27.0 (17.3-38.6)

48.0 (36.5-59.7)

2-sided p:OR: 0.011CB: 0.0068

CR+PR

NC>24wks

CR: 7.7%PR: 40.3%

CR: 2.7%PR: 24.3%

Trastuzumab Remains Effective After Disease Progression

von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.

Combined HER2 Blockade Improves PFS After Progression on Trastuzumab

L N=145

L+T N=146

Progressed or Died, n 128 127

Median, wks 8.1 12.0

Hazard ratio (95% CI) 0.73 (0.57, 0.93)

P value .008

Cum

ulat

ive

% A

live

with

out

Prog

ress

ion

LL+T 13%

28%

0

20

40

60

80

100

0 10 20 30 40 50 60Time from Randomization (wks)

Lapatinib Lapatinib + Trastuzumab Odds Ratio P Value

Response Rate 6.9 10.3 1.5 0.46

CBR 12.4 24.7 2.2 0.01

Blackwell KL, et al. J Clin Oncol. 2010; 28 (7): 1124-30.

Blackwell KL, et al. J Clin Oncol. 2012 Jun 11 [Epub ahead of print].

Updated Overall Survival in ITT

Novel Agents: HER2HER1/2 TKI HKI-272, BIBW 2992, PKI-166, EKB-569Pan HER TKI Canertinib, BMS-599626HER1/2/VEGFR TKI XL647, AEE788HER2 dimerization inhibitor PertuzumabBispecific antibody Ertumaxomab, MM111Conjugated antibodies Trastuzumab-MCC-DM1, trastuzumab-A-Z-CINN

310-paclitaxelTargeted nanoparticles MM302HSP90 inhibitors Tanespimycin, alvespimycin, CNF2024, IPI-504, AUY922,

SNX5422IGF-1R inhibitors (mAb, TKI) CP-751871, EM164, IMC-A12, NVP-ADW742, INSM-18HDAC inhibitors Vorinostat, LBH589, PXD101, NVP-LAQ824, depsipeptide, CI-

994, MS-275 PI3K inhibitors SF1126, BEZ235, XL147, XL765, GDC-0941Akt inhibitors Perifosine, XL418mTOR inhibitors Rapamycin (sirolimus), temsirolimus, everolimus,

deforolimusHER2 vaccines

Investigating T-DM1 (EMILIA): Study Design• Primary endpoints: PFS (independently assessed), OS, safety• Secondary endpoints: PFS (investigator assessment), ORR, OS,

duration of response, time to symptom progression

Women with HER2+

unresectable LABC or MBC(N=991)

Trastuzumab-DM1 3.6 mg/kg q3w IV

(n=495)

Capecitabine 1,000 mg/m2 orally bid, days 1-14, q3w

+Lapatinib

1,250 mg/day orally qd(n=496)

Treatment until disease

progression or unacceptable

toxicity

Stratified by World region, number of prior chemo regimens for MBC, or unresectable

LABC, presence of visceral disease

T-DM1= Trastuzumab-DM1Blackwell KL, et al. Presented at: 2012 Annual ASCO meeting; Abstract LBA1, Abstract S5-5.

T-DM1 Demonstrated Improved Efficacy over Capecitabine + Lapatinib

CAP + LAP(n=495)

T-DM1(n=495)

PFS by Independent Review

6.4 months 9.6 months

HR=0.650; P<0.0001OS (Interim analysis) 23.3 months NRORR 30.8% 43.6%DOR 6.5 months

(95% CI: 5.5,7.2)12.6 months

(95% CI: 8.4,20.8)

Blackwell KL, et al. Presented at: 2012 Annual ASCO meeting; Abstract LBA1, Abstract S5-5.

Case

38-year-old patient presented with inflammatory ER-negative/PgR-negative/HER2-positive breast cancer. She was treated with neoadjuvant AC >TH followed by mastectomy (achieved a pCR) and radiation therapy. She completed 1 year of trastuzumab.

Now, 2 years later, she has disease progression with lung metastases. Biopsy of the largest lesion (2.5 cm) confirms recurrent disease that remains ER-/PgR-/HER2+ by FISH with ratio 8.9. She has a cough but is not SOB. ECOG PS = 1.

Her main goal in therapy is to maximize response and PFS.

Which treatment would you recommend?A. Rechallenge with trastuzumab + capecitabineB. Lapatinib + capecitabineC. Lapatinib + paclitaxelD. Trastuzumab + lapatinibE. Trastuzumab + pertuzumab + docetaxel

ARS Question 4

Which treatment would you recommend?

A. Rechallenge with trastuzumab + capecitabine–Reasonable choice

B. Lapatinib + capecitabine–Reasonable choice

C. Lapatinib + paclitaxel–Incorrect answer

D. Trastuzumab + lapatinib–Reasonable choice

E. Trastuzumab + pertuzumab + docetaxel–Reasonable choice. On June 8, 2012, the FDA approved pertuzumab for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease

ARS Question 4 Response

Pertuzumab and Trastuzumab: Complementary Mechanisms of Action

Trastuzumab:• Inhibits ligand-independent HER2

signaling• Activates ADCC• Prevents HER2 ECD shedding

Pertuzumab:• Inhibits ligand-dependent HER2 dimerization and

signaling• Activates ADCC

Baselga J, et al. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S5-5; Baselga J, et al. J Clin Oncol. 2010;28(7):1138-1144.

HER 1/3/4

HER2

Trastuzumab Pertuzumab

Dimerization domain

Subdomain IV

Pertuzumab Activity:

With trastuzumab

n=66

Monotherapy n=29

% %Best Objective Response

CR 8 0PR 17 7SD 6 months 26 4

ORR 24 7Clinical Benefit Rate 50 11

Baselga J, et al. J Clin Oncol. 2010;28(7):1138-1144.

CLEOPATRA: Study Design

• Primary endpoint: PFS (independently assessed)• Secondary endpoints: PFS (investigator assessment), ORR, OS, Safety

Women with previously untreated, HER2-

positive locally recurrent/metastatic breast

cancer

(N = 808)

Trastuzumab 6 mg/kg q3w* +Docetaxel 75-100 mg/m2 q3w† +

Pertuzumab 420 mg q3w‡

(n = 402)

Trastuzumab 6 mg/kg q3w* +Docetaxel 75-100 mg/m2 q3w† +

Placebo q3w (n = 406)

Treatment until disease progression or

unacceptable toxicity

Stratified by geographic regionand previous (neo)adjuvant chemotherapy

* Trastuzumab 8 mg/kg loading dose given. † Minimum of 6 docetaxel cycles recommended; <6 cycles permitted for unacceptable toxicity or PD.‡ Pertuzumab 840 mg loading dose given.

Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.

CLEOPATRA: Independently Assessed PFS

100

90

80

70

60

50

40

30

20

10

0

Prog

ress

ion-

free

surv

ival (

%)

Time (months)

0 5 10 15 20 25 30 35 40

Ptz + T + D: median 18.5 monthsPbo + T + D: median 12.4 months

HR = 0.6295% CI 0.51-0.75

P<.0001

Stratified by prior treatment status and region.

No. at riskPtz + T+ DPbo + T + D

402406

00

345311

287209

13993

8842

3217

107

00

Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.

CLEOPATRA: Independently Assessed PFS by Predefined Subgroups

Favorspertuzumab

Favorsplacebo

Unstratified analyses.

n

80843237630613511425368112778919480302613763017838840812721767

HR

0.630.630.610.720.510.460.680.650.520.640.550.620.640.680.390.550.960.720.55

0.600.64

95% CI

0.52-0.760.49-0.820.46-0.810.53-0.970.31-0.840.27-0.780.48-0.950.53-0.800.31-0.860.53-0.780.12-2.540.49-0.800.23-1.790.49-0.950.13-1.180.45-0.680.61-1.520.55-0.950.42-0.72

0.49-0.740.53-0.78

AllNo

YesEurope

North AmericaSouth America

Asia<65 years≥65 years<75 years≥75 years

WhiteBlackAsianOther

Visceral diseaseNonvisceral disease

PositiveNegative

IHC 3+FISH-positive

Unknown

0.20 0.4 0.6 1 2

Prior (neo)adjuvant chemotherapy

Region

Age group

Race

Disease type

ER/PgR status

HER2 status

Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.

CLEOPATRA: Response Data

1.5 1.53.8 8.314.6

20.8

74.665.2

5.5 4.2

0

10

20

30

40

50

60

70

80

90

100

Trastuzumab + Docetaxel + Pertuzumab

(n = 343)

Trastuzumab + Docetaxel + Placebo

(n = 336)

CR

PR

SD

PD

Not evaluable

Patie

nts

(%) ORR:

80.2%

ORR: 69.3%

Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.

CLEOPATRA: Safety

Adverse Events,* %Trastuzumab + Docetaxel + Pertuzumab

(n = 407)Trastuzumab + Docetaxel + Placebo

(n = 397)

All Grades Grade 3/4 All Grades Grade 3/4Diarrhea 66.8 7.9 46.3 5.0Alopecia 60.9 NR 60.5 NRNeutropenia 52.8 48.9 49.6 45.8Nausea 42.3 NR 41.6 NRFatigue 37.6 NR 36.8 NRRash 33.7 NR 24.2 NRDecreased appetite 29.2 NR 26.4 NRMucosal inflammation 27.8 NR 19.9 NRAsthenia 26.0 NR 30.2 NRPeripheral edema 23.1 NR 30.0 NRConstipation 15.0 NR 24.9 NRFebrile neutropenia 13.8 13.8 7.6 7.6Dry skin 10.6 NR 4.3 NRLeukopenia NR 12.3 NR 14.6

Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.

CLEOPATRA: Conclusions

• Adding pertuzumab to first-line trastuzumab/docetaxel in HER2+ locally recurrent or MBC improves PFS

• Median PFS prolonged 6.1 months according to IRF– PFS improvement consistent across nearly all patient subgroups

– ORR higher with addition of pertuzumab to trastuzumab/docetaxel

• Pertuzumab associated with increased incidence of mild and manageable diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin

• Incidence of cardiac toxicities comparable between treatment arms

Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.

Case Discussion(Continued)

• She was treated with combined trastuzumab and docetaxel plus pertuzumab on the CLEOPATRA trial. She had an excellent response.

• Docetaxel was discontinued due to increased fatigue and worsening neuropathy after 8 cycles.

• She continued trastuzumab and pertuzumab for another 8 months until she developed increasing headaches associated with nausea.

• Imaging found multiple cerebral lesions with surrounding edema. Systemic disease remained stable.

In addition to steroids and radiation therapy, what would you recommend for this patient at this point?A. No change in therapy B. Discontinue pertuzumab, continue trastuzumab with

lapatinibC. Discontinue pertuzumab, continue trastuzumab with

capecitabineD. Discontinue trastuzumab and pertuzumab. Begin

lapatinib and capecitabine

ARS Question 5

What would you recommend for this patient at this point?A. No change in therapy B. Discontinue pertuzumab, continue trastuzumab with

lapatinibC. Discontinue pertuzumab, continue trastuzumab with

capecitabineD. Discontinue trastuzumab and pertuzumab. Begin

lapatinib and capecitabine–Reasonable choice

ARS Question 5 Response

High Risk of Brain Metastases in Patients With HER2+ MBC

Study IncidenceBendell et al, 2003 34%

Clayton et al, 2004 39%

Stemmler et al, 2006 31%

Kennecke et al, 2010 29% (ER-)15% (ER+)

CNS-Specific Goals for Patients With HER2+ Breast Cancer

• Improve/maintain quality of life– Relieve symptoms– Prevent symptomatic progression– Minimize impact of treatment-related toxicity

• Prolong survival

• Prevention

Studies of Lapatinib + Capecitabine for HER2+ Breast Cancer Brain Metastases

Study Regimen N Prior chemo Prior RT Response criteria

CNS ORR

TTP/PFS OS

Lin et al,CCR 2009*

L + cape 50 81% with >2 T+chemo; PD

on lapatinib monotherapy

100% 50% volNSS, steroids,

lack of non-CNS PD

20% 3.6 mo NR

Boccardo et al, ASCO 2008 (LEAP)

L + cape 138 Prior T required NR Investigator-assessed on

survey

18% Median time on study 2.8

mo

NR

Sutherland et al, Br J Ca 2010 (LEAP)

L + cape 34 82% with >2 chemo for MBC; prior T required

94% RECIST 21% 5.1 mo NR

Metro et al, Ann Oncol 2011

L + cape 22 Median of 2 prior T-based tx for

MBC

86% WHO 32% 5.1 mo 27.9 mo

Lin et al, 2011submitted*

L+ cape 13 Prior T required 100% 50% vol, NSS, steroids, lack of non-CNS

PD

38% NR NR

Bachelot et al, ASCO 2011*

L + cape 45 22% with >2 T+chemo

(31%: no prior T for MBC)

0% 50% vol, NSS, steroids, lack of non-CNS

PD

67% 5.5 mo 91% alive at 6 mo

Her headaches and nausea resolved with steroids. She completed WBRT and began capecitabine and lapatanib.

You explain that the most common toxicity of this combination is: A. AlopeciaB. NauseaC. Hand-foot syndromeD. DiarrheaE. Neutropenia

ARS Question 6

The most common Toxicity of this combination is:A. AlopeciaB. NauseaC. Hand-foot syndromeD. Diarrhea–Correct answerE. Neutropenia

ARS Question 6 Response

Most Frequent Adverse Events (All Grades)

Gr 3

Gr 2

SeverityGr 4

Gr 1

Diarrhea Rash and/or Skin Reaction

% o

f Pat

ient

s

PPE

L+C

L+C

L+CCC

C

10

20

30

40

50

60

70

80

90

100

0

26

19

121

13

15

11

9

28

6

9

20

5

19

132.5

12

117

L = lapatinib; C = capecitabine.

Geyer CE, et al. N Engl J Med. 2006;355(26):2733-2743.

Question and AnswerSession

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