PRO: Pathologic Complete Response Does Predict Outcome for Early Stage Breast Cancer Patients

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1 PRO: Pathologic Complete Response Does Predict Outcome for Early Stage Breast Cancer Patients Amelia B. Zelnak, M.D., M.Sc. Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine

2 Response to Preoperative Chemotherapy Clinical Response Partial Response Complete Response Pathologic Complete Response* B-18: AC x 4 79% 43% 36% 13% B-27: AC x 4 86% 46% 40% 13% B-27: AC x 4 then D x 4 91% 28% 63% 26% * Pathologic Complete Response (pcr) defined as absence of invasive cancer in surgical specimen (breast and axilla); allows for residual ductal carcinoma in situ Rastogi et al, J Clin Oncol 2008;26(5):

3 pcr predicted for favorable long-term outcome NSABP B-18 NSABP B-27 Rastogi et al, J Clin Oncol 2008;26(5):

4 Cortazar et al.: Meta-analysis Sponsor Trials (n) Patients (n) GBG/AGO NSABP EORTC/BIG ITA Total pcr clearly defined Long-term follow-up on recurrence and overall survival available Could pcr be used as a path for using neoadjuvant trials to support FDA approval? Cortazar et al. Lancet 2014.

5 Cortazar: pcr Rates by Tumor Subtype HR + HER2+/HR+ HER2+/HR- TNEG Cortazar et al. Lancet 2014.

6 Cortazar: pcr and Outcome Cortazar et al. Lancet 2014.

7 pcr and Event Free Survival among HR+ Subtype Cortazar et al. Lancet 2014.

8 pcr and Event Free Survival among HER2+ subtype Cortazar et al. Lancet 2014.

9 pcr and Event Free Survival among TNEG Subtype Cortazar et al. Lancet 2014.

10 Pertuzumab Dimerization Domain Pertuzumab Trastuzumab T-DM1 HER2 P P P Lapatinib Neratinib Tyrosine Kinase Domain

11 Pertuzumab: CLEOPATRA Swain et al. Lancet Oncol 2013

12 Pertuzumab: NeoSphere Operable or Locally Advanced/ Inflammatory HER2-positive No prior chemo Tumor > 2 cm N=417 TH (N=107) Docetaxel ( mg/m 2 ) Trastuzumab (8 6 mg/kg) THP (N=107) Docetaxel ( mg/m 2 ) Trastuzumab (8 6 mg/kg) Pertuzumab ( mg) HP (N=107) Trastuzumab (8 6 mg/kg) Pertuzumab ( mg) TP (N=96) Docetaxel ( mg/m 2 ) Pertuzumab ( mg) S U R G E R Y Primary Endpoint pcr rates across arms Secondary Endpoints Clinical Response Disease Free Survival Breast Conservation Rate Patients received FEC x 3 followed by trastuzumab In adjuvant setting Every 3 weeks x 4 Gianni et al. Lancet 2012

13 NeoSphere: pcr rates (breast only) Gianni et al. Lancet 2012

14 NeoSphere: pcr rates Gianni et al. Lancet 2012

15 Pertuzumab: TRYPHAENA Operable or Locally Advanced/ Inflammatory HER2-positive No prior chemo Tumor > 2 cm N=225 N=73 N=75 N=77 Pertuzumab (P) + Trastuzumab (H) x 6 FEC x 3 Docetaxel x 3 FEC x 3 Docetaxel x 3 P + H x 6 Docetaxel x 6 Carboplatin x 6 P +H x 3 S U R G E R Y Primary Endpoint Cardiac Safety Secondary Endpoints pcr rate across arms Patients completed trastuzumab In adjuvant setting Schneeweiss et al. Ann Oncol 2013

16 TRYPHAENA: pcr Rates by HR Status Schneeweiss et al. Ann Oncol 2013

17 Pertuzumab: APHINITY S U R G E R Y Central Confirmation Of HER2 status N = 3806 Accrual 11/11-8/13 R A N D O M I Z A T I O N Chemotherapy Trastuzumab x 1 year Pertuzumab x 1 year Chemotherapy Trastuzumab x 1 year Placebo x 1 year F O L L O W U P

18 FDA Approval of Pertuzumab September 30, 2013: FDA granted accelerated approval to pertuzumab (Perjeta ) for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.

19 CALGB 40603: Carboplatin for Triple Negative Clinical Stage II or III (excluded T4d) ER/PR <10% HER2 negative 2 x 2 randomization Primary Endpoint: pcr Paclitaxel 80 mg/m2 weekly x 12 ddac x 4 Paclitaxel 80 mg/m2 weekly x 12 ddac x 4 Bevacizumab 10/mg/kg q2weeks x 9 Paclitaxel 80 mg/m2 weekly x 12 ddac x 4 Carboplatin AUC 6 q3weeks x 4 Paclitaxel 80 mg/m2 weekly x 12 ddac x 4 Carboplatin AUC 6 q3weeks x 4 Bevacizumab 10/mg/kg q2weeks x 9 S U R G E R Y Sikov et al., SABCS 2013

20 CALGB 40603: pcr Breast/Axilla No Carbo N=212 Carbo N=221 Bev Effect No Bev N=218 39% 49% 44% Bev N=215 43% 60% 52% Carbo Effect 41% 54% Sikov et al., SABCS 2013 Carbo/Bev interaction P=0.43 Carbo Effect: OR 1.71, p= Bev Effect: OR 1.36, p=0.057 Optimal dosing of carboplatin is unclear In contrast to pertuzumab: Adds significant toxicity no survival advantage in metastatic setting Adjuvant trials are in planning stages

21 CALGB 40603: Toxicity Toxicity Chemo (%) Chemo + Bev (%) Chemo + Chemo + Bev/Carbo Carbo (%) (%) Neutropenia Febrile Neutropenia Thrombocytopenia Fatigue Stopped due to Toxicity Sikov et al., SABCS 2013

22 Conclusions You are thoroughly convinced that pcr correlates to long term outcome Larger association in Her2-positive and Triple Negative subtypes Smaller association in less aggressive breast cancers Use of pcr as surrogate endpoint for long-term outcome facilitated quicker FDA approval of pertuzumab Await results of adjuvant pertuzumab trial Given increased toxicity of neoadjuvant carboplatin-containing regimens and lack of survival advantage in the metastatic setting, would carefully select patients for this therapy