Sara Tolaney, MD, MPHDana-Farber Cancer Institute

What’s new with HER2?

All Breast Cancers

Triple negative

15%

ER+65%-75%

HER2+15%-20%

2

Clinical Breast Cancer Subtypes

Goals of Therapy

• Prolong survival • Control cancer symptoms

• Minimize toxicity from therapy

Potential advantages of targeted therapy

• Reduced toxicity

• Improve efficacy

• Prolong disease control

1.0

0.0

0.2

0.4

0.6

0.8

P < 0.001

0 5 10 15 20 25Months

Trastuzumab + CT (n = 235) Median TTP = 7.4 months

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

Pro

babi

lity

Addition of chemotherapy to trastuzumab improves outcomes

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

HER2+ Disease: Major Clinical Advances

• Meaningful progress has been made with novel therapies that are effective and well tolerated

• HER2 remains important target• Resistance is still a major challenge but new

technologies are allowing this to be overcome

1998

TrastuzumabApproved

2002

First PreoperativeTrials Reported Paving

The Way For Use inEarly Stage Disease

2005

Three LargeAdjuvant Trials

Reported

2005

LapatinibApproved

2007-2008

Initial Trialsof T-DM1,Neratinib

2010

PreoperativeTrials of

Dual Blockade

PertuzumabApproved

2012

2013

T-DM1Approved

CLEOPATRA Study Design

HER2-positive MBCcentrally confirmed

(N = 808)

Placebo + trastuzumab

1:1Docetaxel≥ 6 cycles

n = 406

n = 402

Pertuzumab + trastuzumab

Docetaxel≥ 6 cycles

PD

PD

Baselga J, et al. N Engl J Med 2012; 366:109–119.

• Randomization stratified by geographic region and neo/adjuvant chemotherapy

• Study dosing q3w:– Pertuzumab/placebo: 840 mg loading → 420 mg maintenance– Trastuzumab: 8 mg/kg loading → 6 mg/kg maintenance– Docetaxel: 75 mg/m2 → 100 mg/m2 escalation if tolerated

Pertuzumab Delays Progression

ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.

n at risk063787121179284402

06215175110223406Ptz + T + D

Pla + T + D

0

0

0102030405060708090

100PF

S (%

)

0 10 20 30 40 50 8060

Time (months)70

Ptz + T + D: median 18.7 monthsPla + T + D: median 12.4 months

Δ 6.3 months

HR 0.6895% CI = 0.58, 0.80

p < 0.0001

Swain et al, ESMO 2014

Pertuzumab Increases Survival

ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.CI, confidence interval; Pla, placebo; Ptz, pertuzumab.

9

OS

(%)

0102030405060708090

100

0 10 20 30 40 50 7060

Time (months)

HR 0.68 95% CI = 0.56, 0.84

p = 0.0002

Ptz + T + D

Pla + T + D

12810422626831837102391179230289350

n at riskPtz + T + DPla + T + D

402406

40.8 months

56.5months

Δ 15.7 months

Swain et al, ESMO 2014

ORR80.2%

69.3%p=0.001

Side-effects of PertuzumabSafety population Placebo + T + D (n = 396), % Pertuzumab + T + D (n = 408), %Alopecia 60.6 60.8

Diarrhea 48.7 68.4

Neutropenia 50.0 53.4

Nausea 42.4 44.9

Fatigue 37.4 38.0

Rash 24.0 37.5

Asthenia 30.8 27.7

Decreased appetite 26.8 29.7

Peripheral edema 28.0 24.0

Vomiting 24.5 26.0

Myalgia 25.0 24.3

Mucosal inflammation 19.9 27.2

Headache 19.2 25.7

Constipation 25.5 15.9

Upper respiratory tract infection 14.4 20.8

Pruritus 10.1 17.6

Febrile neutropenia 7.6 13.7

Dry skin 6.1 11.3

Muscle spasms 5.1 10.3

Swain et al, ESMO 2014

Pertuzumab• June 2012: FDA approved in

combination with taxane chemotherapy and trastuzumab for patients without prior treatment for MBC

Trastuzumab-DM1 (T-DM1)

1:1 HER2+ MBC

(N=980)

• Prior taxane and trastuzumab

PDT-DM1 3.6 mg/kg q3w IV

Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w

+ Lapatinib

1250 mg/day orally qd

PD

Blackwell et al, ASCO 2012

T-DM1 delays cancer progression

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Cap + LapT-DM1

No. at risk by independent review:

Median (mos) No. eventsCap + Lap 6.4 304T-DM1 9.6 265

Stratified HR=0.650 (95% CI, 0.55, 0.77)P<0.0001

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Prop

ortio

n pr

ogre

ssio

n-fr

ee

Time (mos)

Unstratified HR=0.66 (P<0.0001).Blackwell et al, ASCO 2012

T-DM1 Increase Survival

496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + LapT-DM1

No. at risk: Time (months)

78.4% 64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 360.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n su

rviv

ing

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

Median (months) No. of eventsCap + Lap 25.1 182T-DM1 30.9 149Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006 Efficacy stopping boundary P=0.0037 or HR=0.727

Verma et al, ESMO 2012

T-DM1 is well tolerated• Common side effects:

– Decreased platelet count– Elevated liver tests

• Does not cause typical chemotherapy side effects

• No hair loss• Significant nausea or diarrhea are not common• Does not cause immune suppression

T-DM1• Feb 2013: FDA approved for patients with

MBC and prior taxane and trastuzumab

• Trials at DFCI exploring use of T-DM1 – T-DM1 + GDC0032 (PI3K inhibitor)– T-DM1 + LEE011 (cdk 4/6 inhibitor)– T-DM1 + pembrolizumab (immunotherapy)--

upcoming

17

MM-302: another approach to targeted chemo delivery

• Liposomal doxorubicin (Doxil) is coated with anti-HER2 antibody fragments

– Goal is to direct the liposomes specifically to HER2+ cancer cells and spare normal tissue from toxicity (similar to T-DM1)

• Currently in phase 2 study

Structure

Neratinib

• Oral medication that blocks HER2

• Promising activity seen with

alone and in combination with chemotherapy

• Ongoing study:– capecitabine + lapatinib vs capecitabine + neratinib

CDK 4/6 Inhibitors

• Trials:• LEE011 (ribociclib) + T-DM1 or trastuzumab • Abemaciclib + trastuzumab

What have we learned about therapy after progression on trastuzumab?

• It is important to continue HER2-directed therapy

• Specific chemotherapy is not likely to substantially affect efficacy when combined with trastuzumab

• Single chemotherapy agents rather than doublets are preferred

Continuation of trastuzumab beyond progression

von Minckwitz. JCO 2009

HER2+ locally advanced, MBCProgression during or after trastuzumab therapy

(within 6 weeks of prior trastuzumab)

Capecitabine 2500 mg/m2

days 1-14, 3-week cycle

Capecitabine 2500 mg/m2

days 1-14, 3-week cycle

Trastuzumab 6 mg/kgq 3 weeks

Trastuzumab after progression delays cancer progression

P<0.0467

X : 5.6 (4.2 - 6.3) mosXH : 8.2 (7.3 - 11.2) mos

HR=0.69 (two-sided p=0.034; one-sided p=0.015)

Median Follow-Up: 15.6 monthsvon Minckwitz. JCO 2009

ORR 48% vs 27%, p=0.0011

CNS (brain) metastases in HER2+ MBC

• 30-50% incidence—risk continues over time

• Treatment approach often involves radiation

• Lapatinib: CNS response rate 2-6%

• Lapatinib + capecitabine:– CNS ORR 18-36% in pre-treated pts– CNS ORR 67% in up-front setting

Olson et al, under review; Brufsky et al, CCR 2011; Lin et al, JCO 2008; Lin et al, CCR 2009; Boccardo et al, ASCO 2008; Sutherland et al, Br J Ca 2010; Metro et al, Ann Oncol 2011; Lin et al J Neurooncol 2011; Bachelot et al, ASCO 2011

Testing new therapies for HER2+ breast cancer in the brain

• Phase II study of neratinib + capecitabine

• Phase II study of cabozantinib + herceptin

• Phase II study of abemaciclib + herceptin

• Upcoming study of pembrolizumab + herceptin

Treatment Approach First Line: Taxane + Trastuzumab + Pertuzumab

Second Line: TDM-1

Third, Fourth, Fifth, Sixth Line:Capecitabine + Lapatinib

Capecitabine + TrastuzumabVinorelbine + TrastuzumabLapatinib + Trastuzumab

Pertuzumab + Trastuzumab (?? if no prior Pertuzumab)Other chemotherapy + TrastuzmabEndocrine Therapy + Trastuzumab

From Anatomy…

Lung

Breast

Prostate

Colon

Brain

Genomic/molecular Profiling

A Paradigm Shift: The Genomic View of Cancer

To Genetic Mutation

KIT (Imatinib)

EGFR (Erlotinib)

HER2 (Trastuzumab)

BRAF (Vemurafenib)

PIK3CA(BYL719)

What are clinical trials?• Research studies that are designed to

answer questions about new ways to treat cancer

What are the different types of clinical trials?

Phase PurposePhase I Determine dose

Determine side-effects(Number of people: 15-20)

Phase 2 Determine efficacy(Number of people: <100)

Phase 3 Compare the new treatment to a standard treatmentNumber of people: (100-1000s)

Road To FDA Approval

Preclinical Phase 1 Phase 2 Phase 3FDA

Approval

Dose Escalation in Phase 1 Studies: 3+3 Design

3 Patients10 mg

3 Patients20 mg

3 Patients30 mg EXPANSION COHORT

Enroll 10-20 patients

Once dose determined

Common Questions about Trials

How will you know if the drug is working?

• Frequency of imaging is dependent on the study, but generally every 6-12 weeks

Why should I do a clinical trial?

Weigh Pros and ConsPros:• If a new treatment is proven to work and you are receiving it,

you may be among the first to benefit• You can expand the number of treatment options you have• You have a chance to help others and improve cancer careCons:• New treatments may have side effects that doctors do not

expect • Phase I trials often involve frequent visits during the first

cycle• Even if a new treatment has benefits, it may not work for you

Will my insurance pay for me to participate in the trial?

• Generally, almost all insurance companies pay for patients to participate

• Anything that is for research purposes (ie. research blood, biopsies) is provided by research

• Experimental medication is provided

Conclusion• The number of new drugs in development

is increasing rapidly

• Targeted therapies continue to emerge with the goal of improved effectiveness and decreased side effects