2nd annual San Antonio breast cancer symposium review january 28, 2012 Sponsored By:

SABCS 2011 Review: HER2-Directed Therapy in Breast Cancer Chau 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 Neratinib Pertuzumab 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 HER2 is a member of the EGFR family of proteins and activation of HER2 by as yet unidentified mechanisms leads to downstream signalling cascades that ultimately culminate in cell proliferation, survival, mobility and invasiveness. The monoclonal antibody trastuzumab and the TKI lapatinib are the 2 currently FDA-approved HER2-targeted agents. Hudis NEJM 2007

Trastuzumab in First-Line Treatment 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 vs D+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 Median OS 25.1 vs 20.3 mo* 24.4 mo 31.2 vs 22.7 mo* 28.5 vs 23.9 mo 37.4 vs 37.1 mo Have Slamon, vogel need to check 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 significant 1Slamon 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.

“Other” HER Targeted Strategies There are a number of ways to target EGFR dysregulation. Antibodies against EGFR can act as receptor antagonists and prevent ligand binding, eg, cetuximab. Antibodies may prevent receptor dimerization, eg, trastuzumab (HER2). Antibodies against ligand also block binding, and this approach may be useful when 1 ligand binds to several receptors. Using a small molecule that specifically targets and either reversibly or irreversibly inhibits the tyrosine kinase activity is an approach that may block signaling by all active EGFR forms, including those receptors with mutated or deleted extracellular domains. Erlotinib and gefitinib are 2 ATP-competitive inhibitors of the EGFR tyrosine kinase. Mutations in the tyrosine kinase domain that lead to increased growth factor signaling correlate with increased clinical responsiveness to these TKIs. These mutations demonstrate increased sensitivity to erlotinib and gefitinib. Conjugates of a ligand and a cytotoxic agent (eg, TP-38 and DAB389EGF) or an antibody and a cytotoxic agent (eg, scFv-14e1-ETA fusion toxin) are another approach that may have the advantage of killing the cell after internalization, in addition to inhibiting tyrosine kinase activity. Anti-ligand blocking antibodies Anti-EGFR blocking antibodies cetuximab Tyrosine kinase Inhibitors neratinib lapatinib erlotinib gefitinib HER dimerization inhibitors pertuzumab Ligand- or Ab-toxin conjugates T-DM1 Adapted from Noonberg and Benz. Drugs. 2000;59:753.

Lapatinib

Lapatinib Targets intracellular kinase domain of HER1 and HER2 1+1 2+2 1+2 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 Courtesy of E. Winer 9

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 et al presented the results of the TEACH trial (Tykerb Evaluation after Chemotherapy) in the adjuvant setting. This was a randomized DB, PC phase 3 study to eval effects of delayed L or placebo for up to 12 mo. More than 3000 pts were enrolled who completed neo/adj Rx and who did not receive Tras in adjuvant setting. Med time from dx to study entry was 3 yrs. 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 ? At a med FU was 4 yrs, DFS events occurred in 13% in pts on L vs 17% in placebo arm w/ HR of 0.83 and 2 sided p value of 0.053. Although a numerical improvement in DFS was in favor of L arm, this did not reach the pre-specified stat significance. Thus, there is no role for “delayed” L in adjuvant setting. But, is there a role for “upfront” lapatinib in another adjuvant trail, namely ALTTO? Goss abs S4-7

Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization ALTTO Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Neo (adj) anthracycline-based chemo TL (12 wks) L (40 wks) (L =1500 mg qd) TH (12 wks) THL (12 wks) HL (40 wks) (L =1000 mg qd) TH (12 wks) H (40 wks) Washout (6 wks) This is one design of the ALTTO study, which is the adjuvant study. In this study 8000 pts w/ HER2+ dz are given an anthracycline based treatment and then they are randomized to 1 of 4 arms of Rx as shown, TH arm vs TL-L vs TH then L vs THL-HL arm. Recently, based on the preliminary efficacy analysis by the ALTTO trial independent data monitoring committee, the lapatinib only arm (TL) was closed as it crossed the futility margin and as such its non-inferiority to trastuzumab will not be reached. While the overall study continues, the committee recommended that patients on this arm should be offered trastuzumab (Perez et al. Oral presentation-ASCO Breast Cancer Symposium, September, 2011. It appears that lapatinib “upfront” is inferior to trastuzumab, but we await the results of ALTTO to show if there is any benefit to give L after 3 mo of standard TH or in combination w/ tras as in THL. L (34 wks) (L =1500 mg qd) T=paclitaxel, H=trastuzumab, L=lapatinib 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 years Radiotherapy if indicated

Neratinib

Lapatinib vs Neratinib in 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 Nerat is an irrev Her1/2/4 TKI. Single agent N has clinical activity in MBC-tras-naive of 56% and pretx’d pts of 24%. Comapred w/ L, N’s activity is very promising. However, the most common AE of N is diarrhea. 1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4 Burstein JCO 2010

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 Study Design Neratinib 240 mg/day n = 117 R A N D O M I Z E Phase 2, open-label trial in HER2+ locally advanced or metastatic BC patients L + C L 1,250 mg/day + C 2,000 mg/m2 per day n = 116 1○- PFS 2○ - ORR, CBR, OS, Safety G 3/4 Diarrhea and PPE Originally, this was a phase 3 study powered to assess superiority of N over L+C (N=1000). Due to poor accrual, it was amended to a phase 2 study (N=230) to assess non-inferiority of N against L+C. Pts were randomized 1:1 to N or L+C at doses shown. Non-inf margin in terms of PFS was set at 15% which is equivalent of a 50% benefit of L+C over C in Geyer study. Primary Endpoint-PFS Secondary Endpoint-ORR, CBR, OS, safety, and G ¾ diarrhea and PPE A total of 163 PFS events were needed for analysis w/ the assumptions that: -Med PFS for L+C was 27.5 wks and of N was 33.9 wks (25% improvement in med PFS, HR 0.8) -Enrollment of 3/wk -alpha 0.1, 85% power, 1-yr drop-out rate of 20% 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 Martin et al, SABC 2011 abstract # S5-7 This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute. 16

Key Eligibility Criteria San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 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) Eligibility criteria include: HER2+ Locally adv or MBC 1-2 prior tras-based Rxs Prior taxane and anthr Measuarable dz This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

Baseline Characteristics San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 Baseline Characteristics Characteristic Neratinib (n = 117) L + C (n = 116) Median age (range), y 52 (28–79) 56 (30–79) ER–positive, %b 44 40 PR–positive, %c 27 28 No. of prior anti-cancer regimens, % 1 14 2 33 ≥3 53 Prior trastuzumab therapy, % Adjuvant/neoadjuvant settings 20 32 Metastatic setting 79 68 Baseline Characteristics: well balanced > 50% had > 3 prior Rxs 2030% had prior tras in adjuvant setting 2/3 to 3/4 had tras in MBC setting This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.

Time since randomization (mo) San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 PFS: ITT Population 10 20 30 40 50 60 70 80 90 100 Neratinib L + C Non-inferiority of neratinib vs L+C could not be demonstrated. Probability of PFS (%) 30 5 10 15 20 25 In terms of PFS, the med PFS was higher w/ L+C at 6.8 vs 4.5 mo but this did not reach stat significance. Non-inferiority of neratinib vs L+C could not be demonstrated. The HR for PFS was 1.19 which crossed the 1.15 barrier established for non-inferiority. Time since randomization (mo) n Median PFS 95% CI P value Neratinib 117 4.5 mo 3.1–5.7 mo 0.231 L + C 116 6.8 mo 5.9–8.2 mo L, lapatinib; C, capecitabine; PFS, progression-free survival; CI, confidence interval. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute. 19

Overall Survival: ITT Population San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 Overall Survival: ITT Population 10 20 30 40 50 60 70 80 90 100 Neratinib L + C Probability of OS (%) 5 10 15 20 25 30 OS was numerically higher w/ L+C arm at 23.6 mo vs 19.7 mo, but again this did not reach stat signifcance. Time since randomization (mo) n Median OS 95% CI P value Neratinib 117 19.7 mo 18.2 mo–NE 0.280 L + C 116 23.6 mo 18.0 mo–NE L, lapatinib; C, capecitabine; OS, overall survival; CI, confidence interval; NE, not estimable. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute. 20

Best Overall Response: ITT Neratinib N = 117 L + C N = 116 CR 2% 4% PR 27% 36% SD > 24 wks 15% 23% SD < 24 wks 29% 24% POD 17% 7% Unknown/missing 9% 5% 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. 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) San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 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% Increased ALT 7% 13% Neutropenia 12% In terms of AEs, there was more G 3/4 diarrhea w/ n vs L+C at 28% vs 10%. This was transient and manageable w/ loperamide. There was more G3/4 HFS w/ L+C at 14% vs 0%. There was a low incidence of cardiac events in both treatment arms: neratinib, 7%; L + C, 6% Diarrhea was transient and manageable. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute. 22

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011 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 ? 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. This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute. 23

Pertuzumab

HER2-Targeted Therapy with Pertuzumab Monoclonal antibody and pan-HER inhibitor Binds to a distinct epitope on the HER2 extracellular domain Prevents dimerization Pertuzumab is a humanized monoclonal antibody which binds to the extracellular domain of HER2. However unlike trastuzumab which binds at domain IV, pertuzumab binds domain II of the receptor and is thus able to disrupt HER2 dimerization and ligand-activated signaling with other growth factor receptors, including other HER family members. Animal model studies using HER2 positive breast cancer xenografts have shown a synergistic antitumor activity for pertuzumab in combination with trastuzumab Pertuzumab Trastuzumab

Pertuzumab Activity With trastuzumab N= 661 Monotherapy N= 292 % Best Objective Response CR 8% 0% PR 17% 7% SD 6 months 26% 4% ORR 24% Clinical Benefit Rate 50% 11% Baselga et al published the result of the phase II, single arm study of efficacy and safety of HP in patients with HER2 (+) MBC who had relapsed during tras. The primary endpoints of the study were ORR and CB. Overall, ORR was 24% and clinical benefit rate was 50%. The promising results of the combination of HP led to a protocol amendment to include a 3rd cohort of patients receiving P monotherapy, to assess the activity of P as a single agent. Upon POD on P alone, then patients could have H added to P at the physician’s discretion. Cortes et al reported the result of P as monotherapy. In this study, 29 patients were enrolled, and only 2/29 (7%) patients responded. 1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022

Trastuzumab added back in Pertuzumab Activity With trastuzumab N= 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% Clinical Benefit Rate 50% 11% Fourteen patients then had H added to P, and 2 of 14 (14%) had a response. So P works better when combined w/ H, as dual anti-HER2 therapy ! 1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022

CLEOPATRA: CLinical Evaluation Of Pertuzumab And TRAstuzumab Baselga reported the result of CLEO which was the big news at SABC this past year. CLEO is a randomized, DB, PC, phase 3 study for HER2+pts in the first-line setting. Pts were randomized to TH +Placebo vs THP and it was rec’d that pts receive at least 6 cycles of the taxane. The randomization was stratified by geographic region and prior Rx status. Study dosing for P and H was every 2 weeks as shown. The doce dose was 75 m/m and this was escalated to 100 m/m if tolerated.

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 Eligibility criteria included: Centrally confirmed HER2+ (IHC 3+ and/or FISH > 2.0), locally recurrent, unresectable, or MBC Measurable and/or non-measurable 1 prior hormone Rx for MBC allowed Prior (neo)adj chemo and trastuzumab allowed if DFI > 12 mo LVEF > 50% No h/o CHF or LVEF < 50% during/after prior trastuzumab

Patient Characteristics Placebo + trastuzumab + docetaxel (n = 406) Pertuzumab + trastuzumab + docetaxel (n = 402) Median age, years 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%) Pt characteristics are well balanced. Med was 54 yrs. About 50% were ER/PR +. Almost 50% had received neo adj or adj Rx. Only 10% received adj tras.

Primary endpoint was independently assessed (IA) PFS. 800 pts were required and 381 PFS events were needed to provide 80% power to detect a 33% ↑ in IA-PFS (HR 0.75) at 2-sided p value of 5%. Secondary endpoint was OS. 385 OS events were needed to provide 80% power to detect 33% ↑ in OS (HR 0.75) at 2-sided p value of 5%. Interim OS analysis (estimated at 50% of events for final analysis) was planned at time of IA-PFS analysis. THP > TH in PFS w/ med of 12.4 vs 18.5 mo w/ delta of 6.1 mo. The magnitude of PFS benefit was the highest ever seen, higher than that reported w. the pivotal Slamon and Marty trials. Baselga abs #S5-5

PFS in predefined subgroups This forest plot showed that the addition of P was beneficial regardless of prior neo(adj) Rx or not, region, age group, race, dz type, ER/PR status, and HER2 positivity by IHC or FISH.

Only 10% pts had prior Tras in adj/neoadj setting Only 10% pts had prior Tras in adj/neoadj setting. This is b/c Tras was not approved in 2006 and this study was started in 2008 so many pts did not have Tras in adj setting. Nevertheless, the benefit of P was similar whether pts had prior tras neo(adj) Rx or not w/ HR of 0.6 . Baselga abs #S5-5

Data immature but Baselga abs #S5-5 Interim OS analysis showed a strong trend in favor of P. However, this interim OS analysis did not cross the pre-specified OF stopping boundary of HR <0.0603, p < 0.0012) Thus, OS results are immature and we should await for the mature OS data. Baselga abs #S5-5

Grade 3/4 Adverse Events (incidence > 5%) Placebo + Trastuzumab + Doce N=397 Pertuzumab + Trastuzumab + Doce N=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%) In terms of G 3/4 AEs, there was slightly more neutropenia, FN and diarrhea w/ the addition of P. As noted here, the G 3/ 4 diarrhea incidence was still low well under 10% w/ the addition of P. P is a well tolerated Ab w/ a much lower incidence of diarrhea that than seen w/ the TKIs such as lapatinib or neratinib as discussed previously. G 3/4 diarrhea was low !

Placebo + Trastuzumab + Doce Pertuzumab + Trastuzumab + Doce Cardiac Safety Placebo + Trastuzumab + Doce Pertuzumab + Trastuzumab + Doce Investigator-assessed symptomatic LVSD* 1.8% 1.0% Independently adjudicated Decline in LVEF to < 50% and by > 10% from baseline 6.6% 3.8% There was no increased in cardiac toxicity w/ the addition of P. *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 ? APHINITY adj study

MSKCC IRB# 10-142 THP Schema Accrual Goal = 69 patients N = 69 HER2 + 0-1 prior Rx Tissue bx optional 1° endpoint=6 mo PFS q week …………………………… q 3 weeks…………………………. q 3 weeks…………………………. ♥ ♥ every 4 cycles………………….. TNI, BNP, NRG-1ß every 2 cycles………………………… Paclitaxel at 80 mg/m2 Pertuzumab at 840mg load → 420 mg q 3 w ♥ ECHO w/ strain imaging Trastuzumab at 8 mg/kg load → 6 mg/kg q 3 w PI: Dang 39

APHINITY: Adjuvant Pertuzumab Anthracycline-Based F O L W U P 10 yrs R A N D O M I Z E AC/EC x 4 or FEC/FEC x 3-4 T x 3-4 S U R G E Y Trastuzumab q 3 wks x 52 wks Pertuzumab q 3 wks x 52 wks Centrally Confirm HER2 AC/EC x 4 or FEC/FEC x 3-4 T x 3-4 Trastuzumab q 3 wks x 52 wks Placebo q 3 wks x 52 wks Breast/chest RT and endocrine Rx as appropriate after chemo completion Start w/i 1 wk of randomization Randomize w/i 7 wks of surgery

APHINITY: Adjuvant Pertuzumab Non-Anthracycline Based F O L W U P 10 yrs R A N D O M I Z E TC x 6 S U R G E Y Trastuzumab q 3 wks x 52 wks Pertuzumab q 3 wks x 52 wks Centrally Confirm HER2 TC x 6 Trastuzumab q 3 wks x 52 wks Placebo q 3 wks x 52 wks Breast/chest RT and endocrine Rx as appropriate after chemo completion Start w/i 1 wk of randomization Randomize w/i 7 wks of surgery

Can HER2-targeted antibody therapies be administered safely with anthracyclines?

TRYPHAENA TRYHAENA is a multicenter study to assess tolerability of Neo HP w/ Anthra-Taxane based Rx or carbo-Taxane based Rx in HER2+ BCA pts. 225 pts were rand’d to A) FEC/HP-THP or B) FEC-THP w/ HP after FEC or C) TCH + P After chemo, pts have breast surgery followed by a yr of Tras. Doses of chemo and antibodies are shown here.

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 Median tumor size by CBE, mm (range) Arm A: 53 (10‒220) Arm B: 49 (19‒120) Arm C: 50 (15‒200) ½ HR-neg 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 Median tumor size by CBE, mm (range) Arm A: 53 (10‒220) Arm B: 49 (19‒120) Arm C: 50 (15‒200) ½ HR-neg Schneeweiss abs #S5-6

Baseline Characteristics FEC/HP →THP N=72 FEC →THP N=75 TCHP N=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%) HER2 IHC 2+ 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- HER2 unknown 4 (5.5%) 5 (6.7%) Med age was 49. Half f pts had ER/PR + dz. Most had operable dz.

Schneeweiss abs #S5-6 No pts in Arms A and C had LVSD. 2 pts in Arm B had symptomatic LVSD (or CHF). About 4-5% had LVEF decline of >/= 10% to below 50%. Schneeweiss abs #S5-6

Other Notable G 3/4 AEs Adverse events FEC/HP →THP N=72 FEC →THP N=75 TCHP N=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%) Other notable G 3/4 AEs include: Neutropenia bordering 50% across the 3 arms. FN was higher in Arms A and C when HP was given concurrently w/ all of the chemo’s. Diarrhea appeared higher in the TCHP arm.

Regarding the pCR rate (no invasive cancer, DCIS allowed), it was 62% vs 57 % vs 66 % in Arms A, B, and C. Regarding a conservative pCR rate (no invasive CA or DCIS), it was 51% vs 45% vs 52% in Arms A, B, and C.

Breast Conserving Surgery When Mastectomy Was Planned* FEC/HP →THP N=46 FEC →THP N=36 TCHP N=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%) For those w/ T2-3 tumors for whom mastectomy was planned, the BCS rate was around 20% across the 3 arms. * 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. 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

Loibl et al for GBG and AGO-B Study groups 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

Von Minckwitz et al reported the meta-analysis of neoadjuvant trials at ASCO 2011. All pts received anthra-taxane based Rx. I’d like to draw your attention to the bottom 2 trials (TECHNO tral and Geparquattro trial) in which HER2 + pts receive Tras w/ chemo. As you can see, the pCR appears higher in the 23-29% than those who are HER2-.

Objectives Define 3 subgroups: Compare DDFS and OS in these subgroups HER2+ w/ trastuzumab HER2+ w/o trastuzumab HER2- Compare DDFS and OS in these subgroups pCR vs no pCR Hormone receptor + vs -tumors They defined 3 subgroups as shown and compared HER2 + w/ tras w/ Her2 + w/o tras and HER2 + w/ tras to HER2- group. They compared DDDFS and OS in these subgroups relative to pCR vs no pCR and HER2+ vs – status.

The flow of pts are outlined here. Over 6300 pts were available Of these, over 4300 were eligible due to known HER2 status. Over 300 were HER2- w/ pCR rate of 14.8%. Over 600 were HER2+ who did NOT receive Tras w/ pCR rate of 17.9%. Over600 were HER2+ who received Tras w/ a pCR rate of 27.3%.

Patients’ Characteristics Age 49 (22-81) yrs cT1-3 87% cN+ 53% IDC 82% Grade 3 40% Hormone Receptor + 66% HER2- 70% Med age was 49. Majority had operable dz. Clinical nodal involvement was present in 53%. 2/3 were HR+ 70% was HER2-.

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-

When 3 subgroups were compared together in terms of no pCR and pCR. Pink-HER2+ w/ tras Green-HER2+ w/o tras Blue-HER2- On left hand side, there was no stat significance in difference in all 3 groups. However, when looking at the her2+ w/ tras in pink, the event rate was ½ of that seen in Her2+ group w/o tras in green. On right hand side, in the pCR groups, the HER2+ group w/ tras had the lowest event rate and was stat signif better than Her2 + group w/o tras. Loibl abs #S5-4

When looking at DDFS on left and OS on right in all 3 subgroups, in terms of HR+ status, all curves are superimposed. There is no stat signif.

However, when looking at DDFS on left and OS on right in all 3 subgroups in terms of HR- status, the HER2+ w/ tras had better DDFS over her2+ w/o tras and HER2-. In terms of OS, HER2+ w/ tras had better OS than Her2- group. This speaks to the effectiveness of tras in HER2+ group !

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 !

2nd annual San Antonio breast cancer symposium review january 28, 2012 Sponsored By: