sponsored by:. sabcs 2011 review: her2-directed therapy in breast cancer chau dang, md assistant...

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SABCS 2011 Review:HER2-Directed Therapy in

Breast CancerChau Dang, MD

Assistant Professor of Medicine

Weill Cornell Medical College

Breast Cancer Medicine Service

Memorial Sloan-Kettering Cancer Center

January 28, 2012

Objectives• Overview on Trastuzumab• Lapatinib

– Goss et al (abstract # S4-7)

• Neratinib– Martin et al (abstract # S5-7)

• Pertuzumab– Baselga et al (abstract # S5-5)– Schneeweiss et al (abstract # S5-6)

• pCR as predictor of outcomes– Loibl et al (abstract # S5-4)

HER2-“Positive” Breast Cancer• 20-25% of invasive breast cancers• Overexpression can activate signaling• Promotes cell proliferation and survival

Hudis NEJM 2007

Studies Slamon et al,

20011

Vogel et al,

20022

Burstein et al, 20033

Marty et al, 20054

Kaufman et al, 20095

Valero et al 20116

N 469 114 54 186 207 263

Treatment AC/EC + H or T+H vs chemo

H VH D+H vs

D

Anas + H vs

Anas DCbH vsD+H

Response Rate

50% vs 32%* 35% (IHC 3+)

34% (FISH+)68% 61% vs

34%*20.3% vs 6.8%*

72% vs 72%

Median TTP

7.4 vs 4.6 mo*

3.8 mo (H at 4 mg/kg)

3.5 mo

(H at 2 mg/kg)

NR 11.7 vs 6.1 mo*

4.8 vs

2.4 mo*10.3 vs 11.1 mo

Median PFS

NR NR NR NR 4.8 vs

2.4 mo*NR

Median OS 25.1 vs 20.3 mo*

24.4 mo NR 31.2 vs 22.7 mo*

28.5 vs 23.9 mo

37.4 vs 37.1 mo

Trastuzumab in First-Line Treatment

AC, anthracycline + cyclophosphamide; Anas, anastrozole; T, paclitaxel; D, docetaxel; EC, epirubicin + cyclophosphamide; H, trastuzumab; mo, months; PFS, progression-free survival; OS, overall survival; RR, response rate; TTP, time to progression; VH, vinorelbine + trastuzumab; *statistically significant1Slamon DJ et al. N Engl J Med. 2001:344(11):783-792; 2Vogel CL et al. J Clin Oncol. 2002;20:719-726; 3Burstein HJ et al. J Clin Oncol. 2003;21(15):2889-2895; 4Marty M et al. J Clin Oncol. 2005;23(19):4265-4274; 5Kaufman B et al. J Clin Oncol. 2009;27(33):5529-5537; 6Valero V et al. J Clin Oncol. 2011;29:149-156.

6

“Other” HER Targeted Strategies

HER dimerizationinhibitors

pertuzumab

Anti-EGFRblocking

antibodies

cetuximab

Anti-ligandblocking

antibodiesTyrosinekinase

Inhibitors

neratiniblapatiniberlotinib gefitinib

Ligand- or Ab-toxin

conjugates

T-DM1Adapted from Noonberg and Benz. Drugs. 2000;59:753.

Lapatinib

Lapatinib

• Targets intracellular kinase domain of HER1 and HER2

• Reversible inhibition of HER1 and HER2 homo and heterodimer formation

• Inhibits growth in trastuzumab conditioned cell lines

1+1 2+2 1+2

Courtesy of E. Winer

Clinical Activity of Lapatinib in HER2+ MBC

ORR

Monotherapy in trastuzumab-refractory MBC1,2

4-8%

Monotherapy in trastuzumab-naive MBC3

≈24%

With chemo (capecitabine) in chemo & trastuzumab-refractory MBC4,5

24% (vs 14% with X alone)

With chemo (paclitaxel) in first-line MBC setting6

63% (vs 38% with T alone)

1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4Geyer NEJM 2006; 5Cameron BrCancerResTreat 2008; 6Di leo JCO 2008

TEACH trial: Tykerb Evaluation After

Chemotherapy• Randomized, double-blind, placebo-controlled, phase III

trial to evaluate the effects of delayed adjuvant lapatinib monotherapy

• More than 3000 women– completed neo-adjuvant or adjuvant chemotherapy, – did not receive trastuzumab and – NED

• Randomized to lapatinib or placebo for up to 12 months or until a DFS event

• Median time from diagnosis to study entry: 3 years

Goss abs S4-7

Delayed Adjuvant Lapatinib Results

• Median follow up of 4 years

• DFS events were 13% vs. 17% in favor of lapatinib vs placebo (HR = 0.83 95% CI, 0.70 to 1.00; 2 sided p=0.053), but not statistically significant.

• No role for “delayed” lapatinib in the adjuvant setting !

• What about “upfront” lapatinib in ALTTO ?

Goss abs S4-7

•Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 yearsafter the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years• Radiotherapy if indicatedRadiotherapy if indicated

ALTTOALTTO

TH (12 wks)TH (12 wks)

H (40 wks)H (40 wks)

TL (12 wks)TL (12 wks)

L (40 wks)L (40 wks)

(L =1500 mg qd) (L =1500 mg qd)

TH (12 wks)TH (12 wks) THL (12 wks)THL (12 wks)

HL (40 wks)HL (40 wks)

(L =1000 mg qd)(L =1000 mg qd)

Washout (6 wks)Washout (6 wks)

L (34 wks)L (34 wks)

(L =1500 mg qd)(L =1500 mg qd)

Adjuvant Lapatinib and/or Trastuzumab Treatment

Optimization

Neo (adj) anthracycline-based chemo

T=paclitaxel, H=trastuzumab, L=lapatinib

Neratinib

Lapatinib vs Neratinibin HER2+ MBC

Lapatinib ORR Neratinib ORR

Monotherapy in H-refractory MBC

4-8%1,2 24%4

Monotherapy in H-naive MBC

≈24%3 56%4

1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4 Burstein JCO 2010

Phase 2, open-label trial in HER2+ locally

advanced or metastatic BC

patients

Neratinib 240 mg/day

n = 117

L + CL 1,250 mg/day +

C 2,000 mg/m2 per day n = 116

RANDOMIZE

Study Design

Neratinib was administered orally at 240 mg/day continuously

L 1,250 mg/day was administered orally continuously;

C 2,000 mg/m2 was administered orally on D1 to 14 of each 21-day cycle

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011

This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

Martin et al, SABC 2011 abstract # S5-7

1○- PFS2○ - ORR, CBR, OS, Safety G 3/4 Diarrhea and PPE

Key Eligibility Criteria• Women with HER2+ locally advanced or metastatic BC not

amenable to curative therapy

• Disease progression on or following 1 to 2 prior trastuzumab-based regimens

• Prior treatment with a taxane regimen

• Prior anthracycline treatments at or below the maximum cumulative dose of 400 mg/m2 for doxorubicin, 800 mg/m2 for epirubicin, or equivalent dose for other anthracycline derivatives

• Measurable disease (≥1 measurable lesion), as defined by Response Evaluation Criteria in Solid Tumors (RECIST)

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011

This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

Baseline Characteristics

CharacteristicNeratinib(n = 117)

L + C(n = 116)

Median age (range), y 52 (28–79) 56 (30–79)ER–positive, %b 44 40PR–positive, %c 27 28No. of prior anti-cancer regimens, % 1 14 14 2 33 33 ≥3 53 53Prior trastuzumab therapy, % Adjuvant/neoadjuvant settings 20 32 Metastatic setting 79 68

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011

This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

0 305 10 15 20 250

10203040506070809010

0

PFS: ITT Population

n Median PFS 95% CI P valueNeratinib 117 4.5 mo 3.1–5.7 mo

0.231L + C 116 6.8 mo 5.9–8.2 moL, lapatinib; C, capecitabine; PFS, progression-free survival; CI, confidence interval.

Time since randomization (mo)

Pro

babi

lity

of P

FS

(%

)NeratinibL + C

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011

This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

Non-inferiority of neratinib vsL+C could not be demonstrated.

010203040506070809010

0

0 5 10 15 20 25 30

Overall Survival: ITT Population

n Median OS 95% CI P valueNeratinib 117 19.7 mo 18.2 mo–NE

0.280L + C 116 23.6 mo 18.0 mo–NEL, lapatinib; C, capecitabine; OS, overall survival; CI, confidence interval; NE, not estimable.

Time since randomization (mo)

Pro

babi

lity

of O

S (

%)

NeratinibL + C

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011

This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

Best Overall Response: ITT

NeratinibN = 117

L + CN = 116

CR 2% 4%

PR 27% 36%

SD > 24 wks 15% 23%

SD < 24 wks 29% 24%

POD 17% 7%

Unknown/missing 9% 5%

L=lapatinib, C=capecitabine

The ORR was 40% in L+C arm vs 29% in neratinib arm.The CBR was 63% in L+C arm vs 44% in neratinib arm.

Selected Treatment-related AEs (All Grades)

Neratinib (n = 116)

L + C (n = 115)

Adverse event, %

Diarrhea

85%

(28% G 3/4)

68%

(10% G 3/4)

PPE

5%

(0% G 3/4)

65%

(14% G 3/4)

Nausea 35% 38%Vomiting 24% 17%Rash 19% 34%Fatigue 16% 23%Hyperbilirubinemia 1% 23%Increased ALT 7% 13%Neutropenia 5% 12% There was a low incidence of cardiac events in both treatment arms:

neratinib, 7%; L + C, 6%

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011

This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

Diarrhea was transient and manageable.

Conclusions• Neratinib did not demonstrate non-inferiority for PFS

against L+C.

• Med PFS was numerically (not statistically) superior with L+C (6.8 mo vs 4.5 mo).

• Diarrhea was the most frequently reported AE.

• The ORR of neratinib in heavily pretreated patients was 29%, consistent with results from the preceding single-arm trial.1

• Continued development of neratinib as monotherapy and in combination with other agents for treatment of recurrent HER2+ BC ?

1. Burstein HJ, et al. J Clin Oncol. 2010;28(8):1301-1307.

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011

This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

Pertuzumab

HER2-Targeted Therapy with Pertuzumab

• Monoclonal antibody and pan-HER inhibitor

• Binds to a distinct epitope on the HER2 extracellular domain

• Prevents dimerization

Trastuzumab Pertuzumab

Pertuzumab Activity

1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022

With trastuzumabN= 661

Monotherapy N= 292

% %

Best Objective Response

CR 8% 0%

PR 17% 7%

SD 6 months

26% 4%

ORR 24% 7%

Clinical Benefit Rate

50% 11%

Pertuzumab ActivityWith

trastuzumabN= 661

Monotherapy N= 292

Trastuzumab added back in

N=142

% % %

Best Objective Response

CR 8% 0%

PR 17% 7% 14%

SD 6 months

26% 4%

ORR 24% 7% 14%

Clinical Benefit Rate

50% 11%

1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022

CLEOPATRACLEOPATRA: CLinical Evaluation Of

Pertuzumab And TRAstuzumab

Eligibility Criteria

• Centrally confirmed HER2+ (IHC 3+ and/or FISH > 2.0)• Locally recurrent, un-resectable, or MBC• Measurable and/or non-measurable• 1 prior hormone Rx for MBC allowed• Prior neoadj/adj chemo and trastuzumab allowed if DFI >

12 mo• LVEF > 50%• No h/o CHF or LVEF < 50% during/after prior

trastuzumab

Patient CharacteristicsPlacebo +

trastuzumab + docetaxel(n = 406)

Pertuzumab + trastuzumab +

docetaxel(n = 402)

Median age, years 54y 54y

ER- and/or PR-positive

199 (49%) 189 (47%)

Prior (neo)adjuvant chemotherapy

192 (47%) 184 (46%)

Components of neoadj/adj therapy Anthracycline Hormones Taxane Trastuzumab

164 (40%)97 (24%)94 (23%)41 (10%)

150 (37%)106 (26%)91 (23%)47 (12%)

Baselga abs #S5-5

PFS in predefined subgroups

Baselga abs #S5-5

Data immature but

Baselga abs #S5-5

Grade 3/4 Adverse Events(incidence > 5%)

Adverse Events Placebo + Trastuzumab +

DoceN=397

Pertuzumab + Trastuzumab +

DoceN=407

Neutropenia 182 (45.8%) 199 (48.9%)

Febrile neutropenia 30 (7.6%) 56 (13.8%)

Leukopenia 58 (14.6%) 50 (12.3%)

Diarrhea 20 (5.0%) 32 (7.9%)

G 3/4 diarrhea was low !

Cardiac Safety

Placebo + Trastuzumab + Doce

Pertuzumab + Trastuzumab + Doce

Investigator-assessedsymptomatic LVSD*

1.8% 1.0%

Independently adjudicatedsymptomatic LVSD*

1.0% 1.0%

Decline in LVEF to < 50% and by > 10% from baseline

6.6% 3.8%

*LVSD=left ventricular systolic dysfunction, defined as NYHA class III/IV

Conclusions• CLEOPATRA met its primary endpoint w/ a statistically

significant PFS improvement from 12.4 to 18.5 months w/ addition of pertuzumab (HR 0.62, p < 0.0001).

• OS data immature

• Pertuzumab well tolerated

• No increased cardiac toxicity

• May be practice changing !

Questions

• Safe in combination with other chemotherapy foundations?

• Adjuvant/neoadjuvant studies ?

• Continuation beyond progression ?

MSKCC IRB# 10-142THP Schema

Accrual Goal = 69 patients

♥ ♥ every 4 cycles………………….. TNI, BNP, NRG-1ß every 2 cycles…………………………

q week ……………………………

q 3 weeks………………………….

q 3 weeks………………………….

Paclitaxel at 80 mg/m2

Pertuzumab at 840mg load → 420 mg q 3 w

Trastuzumab at 8 mg/kg load → 6 mg/kg q 3 w

N = 69HER2 +0-1 prior RxTissue bx optional1° endpoint=6 mo PFS

♥ ECHO w/strain imaging

PI: Dang

APHINITY: Adjuvant PertuzumabAnthracycline-Based

S R

FOLLOWUP

10yrs

T x 3-4AC/EC x 4 orFEC/FEC x 3-4

Trastuzumab q 3 wks x 52 wks

Pertuzumab q 3 wks x 52 wks

AC/EC x 4 orFEC/FEC x 3-4

T x 3-4

Trastuzumab q 3 wks x 52 wks

Placebo q 3 wks x 52 wks

SURGERY

RANDOMIZE

CentrallyConfirm HER2

Randomize w/i 7 wks of surgeryStart w/i 1 wk of randomization

Breast/chest RT and endocrine Rx as appropriate after chemo completion

APHINITY: Adjuvant PertuzumabNon-Anthracycline Based

S R

FOLLOWUP

10yrs

TC x 6

Trastuzumab q 3 wks x 52 wks

Pertuzumab q 3 wks x 52 wks

TC x 6

Trastuzumab q 3 wks x 52 wks

Placebo q 3 wks x 52 wks

SURGERY

RANDOMIZE

CentrallyConfirm HER2

Randomize w/i 7 wks of surgeryStart w/i 1 wk of randomization

Breast/chest RT and endocrine Rx as appropriate after chemo completion

Can HER2-targeted antibody therapies be administered

safely with anthracyclines?

TRYPHAENA

Study Endpoints• Primary endpoint:

– Cardiac safety• Symptomatic LVSD (grade ≥3)• LVEF declines (≥10 percentage points and below

50%)• Secondary endpoints:

– Toxicity

– pCR

– Clinical response rate

– Rate of BCS

– DFS, OS

– Biomarker evaluation

Schneeweiss abs #S5-6

Eligibility Criteria

• Centrally confirmed HER2-positive locally advanced, inflammatory, or early-stage breast cancer

• Primary tumor ≥2 cm• Baseline LVEF ≥55%• ECOG PS 0 or 1• No previous anticancer therapy or radiotherapy

for any malignancy• Adequate bone marrow, liver, and renal function

Schneeweiss abs #S5-6

Baseline CharacteristicsFEC/HP →THP

N=72FEC →THP

N=75TCHPN=76

Med age, yrs (range) 49 (27-77) 49 (24-75) 50 (30-81)

ECOG 0 65 (91.5%) 66 (88.0%) 67 (88.2%)

ECOG 1 6 (8.5%) 9 (12.0%) 9 (11.8%)

ER and/or PR + 39 (53.4%) 35 (46.7%) 40 (51.9%)

ER and/or PR- 34 (46.6%) 40 (53.3%) 36 (48.1%)

Disease Type

Operable 53 (72.6%) 54 (72.0%) 49 (63.6%)

LABC 15 (20.5%) 17 (22.7%) 24 (31.2%)

IBC 5 (6.8%) 4 (5.3%) 4 (5.2%)

HER2 IHC 0 and 1+ 1 (1.4%) 0 (0.0%) 0 (0.0%)

HER2 IHC 2+ 5 (6.8%) 1 (1.3%) 2 (2.6%)

HER2 IHC 3+ 67 (91.8%) 74 (98.7%) 75 (97.4%)

HER2 FISH + 69 (94.5%) 69 (92.0%) 73 (94.8%)

HER2 FISH- 0 (0.0%) 1 (1.3%) 2 (2.6%)

HER2 unknown 4 (5.5%) 5 (6.7%) 2 (2.6%)

Schneeweiss abs #S5-6

Other Notable G 3/4 AEs

Adverse events

FEC/HP →THPN=72

FEC →THPN=75

TCHPN=76

Neutropenia 34 (47.2%) 32 (42.7%) 35 (46.1%)

Febrile neutropenia

13 (18.1%) 7 (9.3%) 13 (17.1%)

Leukopenia 14 (19.4%) 9 (12.0%) 9 (11.8%)

Diarrhea 3 (4.2%) 4 (5.3%) 9 (11.8%)

Breast Conserving Surgery When Mastectomy Was Planned*

FEC/HP →THPN=46

FEC →THPN=36

TCHPN=37

Achieved(95% CI)

10 (21.7%)(10.9-36.4)

6 (16.7%)(6.4-32.8)

10 (27.0%)(13.8-44.1)

Not Achieved 36 (78.3%) 30 (83.3%) 27 (73.0%)

* Patients in ITT population w/ T2-3 tumors for whom mastectomy was planned.

Conclusions• Low incidence of symptomatic/asymptomatic LVSD across

all arms:– Concurrent admin of HP w/ Epi resulted in similar cardiac

tolerability compared with sequential admin or the anthracycline-free regimen

• Neutropenia, FN, leukopenia, and diarrhea were the most frequent G 3/4 AEs across all arms.

• High pCR rates (57- 66%) w/ HP, regardless of chemotherapy chosen

• TRYPHAENA supports ongoing APHINITY study, a Phase III trial to evaluate HP + standard chemo in adjuvant setting.

Schneeweiss abs #S5-6

Comparison of OS according to pCR in Pts w/ HER2+ BCA

Receiving Neoadjuvant Chemo w/ and w/o Trastuzumab Compared

w/ Pts w/ HER2- Tumors

Loibl et al for GBG and AGO-B Study groups

pCR in HER2 + BCA

• pCR is a surrogate for DFS and OS in pts w/ HER2+ BCA treated w/ neoadjuvant chemo w/ or w/o trastuzumab.1

• Pts w/ pCR after neoadjuvant chemo + trastuzumab have excellent DFS and OS.2

1. Gianni, Lancet 2010; 2. Untch, JCO 2011

Objectives

• Define 3 subgroups:– HER2+ w/ trastuzumab– HER2+ w/o trastuzumab– HER2-

• Compare DDFS and OS in these subgroups– pCR vs no pCR– Hormone receptor + vs -tumors

Patients’ Characteristics

Age 49 (22-81) yrs

cT1-3 87%

cN+ 53%

IDC 82%

Grade 3 40%

Hormone Receptor + 66%

HER2- 70%

pCR > No pCR

• DDFS and OS were better in pCR vs no pCR groups in all 3 subgroups:

– HER2+ w/ tras– HER2+ w/o tras– HER2-

Loibl abs #S5-4

Author’s Conclusions• HER2+ pts w/ tras + chemo had higher pCR.

• DDFS and OS was better in pCR group than no pCR group in all 3 subgroups (HER2+ w/ tras, HER2+ w/o tras, HER2-).

• In pCR pts, OS was better in HER2+ pts w/ tras than HER2+ pts w/o tras.

• In hormone receptor- group, HER2+ pts w/ tras have better outcomes than HER2+ w/o tras and HER2- groups. Trastuzumab is effective !

• pCR can be surrogate marker for HER2+ disease.

Summary• No role for “delayed” adjuvant lapatinib

– ALTTO may define role of lapatinib ?

• Neratinib did not demonstrate non-inferiority for PFS against L+C. – Main toxicity was diarrhea.

• Pertuzumab added to standard docetaxel + trastuzumab improves PFS ! – Maybe new standard of care !

– Adjuvant study APHINITY open !

Summary

• No increased cardiac toxicity when HP given concurrently w/ epi-taxane Rx and carbo-taxane Rx.– However, concurrent anthracycline with trastuzumab

or pertuzumab should not be given outside of clinical trial.

• What to do for those w/ no PCR?– Need trials designed to assess utility of novel or

optimal Rx for those w/o pCR

Thank You !

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