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

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1 PO: Pathologic Complete esponse Does Predict Outcome for Early Stage Breast Cancer Patients Amelia B. Zelnak, MD, MSc Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Disclosures Nothing relevant to disclose. 1

2 esponse to Preoperative Chemotherapy Clinical esponse Partial esponse Complete esponse Pathologic Complete esponse* 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 esponse (pc) defined as absence of invasive cancer in surgical specimen (breast and axilla); allows for residual ductal carcinoma in situ astogi et al, J Clin Oncol 2008;26(5): pc predicted for favorable long term outcome NSABP B 18 NSABP B 27 astogi et al, J Clin Oncol 2008;26(5):

3 Cortazar et al.: Meta analysis Sponsor Trials (n) Patients (n) GBG/AGO NSABP EOTC/BIG ITA Total pc clearly defined Long term follow up on recurrence and overall survival available Could pc be used as a path for using neoadjuvant trials to support FDA approval? Cortazar: pc ates by Tumor Subtype H + HE2+/H+ HE2+/H TNEG 3

4 Cortazar: pc and Outcome pc and Event Free Survival among H+ Subtype 4

5 pc and Event Free Survival among HE2+ subtype pc and Event Free Survival among TNEG Subtype 5

6 Pertuzumab: NeoSphere Operable or Locally Advanced/ Inflammatory HE2 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 G E Y Primary Endpoint pc rates across arms Secondary Endpoints Clinical esponse Disease Free Survival Breast Conservation ate Patients received FEC x 3 followed by trastuzumab In adjuvant setting Every 3 weeks x 4 Gianni et al. Lancet 2012 NeoSphere: pc rates (breast only) Gianni et al. Lancet

7 NeoSphere: pc rates Gianni et al. Lancet 2012 Pertuzumab: TYPHAENA Operable or Locally Advanced/ Inflammatory HE2 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 G E Y Primary Endpoint Cardiac Safety Secondary Endpoints pc rate across arms Patients completed trastuzumab In adjuvant setting Schneeweiss et al. Ann Oncol

8 TYPHAENA: pc ates by H Status Schneeweiss et al. Ann Oncol 2013 Pertuzumab: CLEOPATA Swain et al. Lancet Oncol

9 Pertuzumab: APHINITY S U G E Y Central Confirmation Of HE2 status N = 3806 Accrual 11/11 8/13 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 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 HE2 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. 9

10 CALGB 40603: Carboplatin for Triple Negative Clinical Stage II or III (excluded T4d) E/P <10% HE2 negative 2 x 2 randomization Primary Endpoint: pc 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 G E Y Sikov et al., SABCS 2013 CALGB 40603: pc 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: O 1.71, p= Bev Effect: O 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 10

11 CALGB 40603: Toxicity Chemo + Chemo Chemo + Chemo + Bev/Carbo Toxicity (%) Bev (%) Carbo (%) (%) Neutropenia Febrile Neutropenia Thrombocytopenia Fatigue Stopped due to Toxicity Sikov et al., SABCS 2013 Conclusions You are thoroughly convinced that pc correlates to long term outcome Larger association in Her2 positive and Triple Negative subtypes Smaller association in less aggressive breast cancers Use of pc 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 11