Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: outcomes from CALGB (Alliance) William M Sikov, Donald A Berry, Charles M Perou, Baljit Singh, Constance T Cirrincione, Sara M Tolaney, George Somlo, Elisa R Port, Rubina Qamar, Keren Sturtz, Eleftherios Mamounas, Mehra Golshan, Jennifer R Bellon, Deborah Collyar, Olwen M Hahn, Lisa A Carey, Clifford A Hudis, Eric P Winer for the CALGB/Alliance San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CALGB 40603: Schema – Randomized phase II Paclitaxel 80 mg/m 2 wkly x 12 ddAC x 4 Bevacizumab 10 mg/kg q2wks x 9 Carboplatin AUC 6 q3wks x 4 Paclitaxel 80mg/m 2 weekly x 12 Surgery & * XRT* No Adjuvant Systemic Treatment Planned* Paclitaxel 80 mg/m 2 wkly x 12 Research biopsies- frozen and fixed 2 X 2 Randomization ddAC x 4 & Research biopsies if residual tumor *MD discretion CALGB 40603: Schema – Randomized Phase II San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute. B A C D Arm

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2015 This presentation is the intellectual property of William Sikov, MD. Contact at for permission to reprint or distribute. CALGB – pCR Results by factor pCR Breast ypT0/is (%, 95% CI) OverallCarboNo CarboORp-value 53 (49-58) 60 (54-66)46 (40-53) BevNo BevORp-value 59 (52-65)48 (41-54) pCR Breast/Axilla ypT0/is ypN0 (%, 95% CI) OverallCarboNo CarboORp-value 48 (43-53) 54 (48-61)41 (35-48) BevNo BevORp-value 52 (45-58)44 (38-51) Sikov et al, J Clin Oncol 2015

Definition of endpoints Event-free survival (EFS) – Study entry to ipsilateral invasive breast or other locoregional recurrence, distant recurrence or death from any cause Overall Survival (OS) – Study entry to death from any cause Median follow-up: 39 months (maximum 66 months) 110 EFS events and 77 OS deaths Data on systemic treatment received in adjuvant setting (if any) was not collected CALGB – Long-term follow-up San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CALGB – Event-Free and Overall Survival San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

pCR Breast pCR Breast/Axilla or RCB I* Yes/No N (%) 231 (52%) /212 (48%) 207 (47%) /236 (53%) 266 (60%) /177 (40%) EFS-HR0.33 ( )0.30 ( )0.29 ( ) OS-HR0.28 ( )0.20 ( )0.21 ( ) CALGB – EFS and OS by Response * RCB I = Residual Cancer Burden Class I per Symmans et al, JCO 2007 San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CALGB – EFS by pCR Breast/Axilla San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CALGB – OS by pCR Breast/Axilla San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

From FDA-requested meta-analysis Cortazar et al Lancet 2014 Impact of pCR Breast/Axilla on EFS in TNBC San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute. From meta-analysis; CALGB superimposed pCR rates 47.8% (40603) vs. 33.6% (meta-analysis)

CALGB – EFS/OS Events by Response San Antonio Breast Cancer Symposium, December 8-12, 2015 At 3 years, patients who achieved pCR Breast/Axilla (47% overall) had much lower rates of –Ipsilateral invasive breast recurrences 2.9% (vs 13.3%) –Other locoregional recurrences 1.5% (vs. 6.6%) –Distant recurrences 9.2% (vs. 26.5%) –All deaths 6.8% (vs. 28.3%) –Breast cancer attributed deaths 5.8% (vs. 25.2%) This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CarboplatinBevacizumab YesNoYesNo EFS 3-year76%71%75%72% HR0.84 ( )0.80 ( ) OS 3-year81%85% 81% HR1.15 ( )0.76 ( ) CALGB – EFS and OS by Factor San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CALGB – EFS for carboplatin vs. not San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CALGB – EFS for bevacizumab vs. not San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

∆ pCR Breast/Axilla vs. predicted EFS HR in TNBC Derived from Cortazar et al Adapted from Berry & Hudis, JAMA Oncology 2015 San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

Event typeOverall Factor CarboNo CarboBevNo Bev Patients EFS Events Ipsilateral Inv Br Rec Other LRR Distant Recurrence 8040 OS Events Breast Cancer Death Non-BC, non-Rx Death Unknown Death CALGB – EFS/OS Events by Factor San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CALGB/Alliance 40603: Summary Achievement of pCR with weekly paclitaxel followed by ddAC +/- carboplatin and/or bevacizumab is associated with significant improvements in EFS and OS Addition of RCB I patients does not diminish the prognostic significance associated with pCR Breast/Axilla –Substantial reductions are seen in both LRR and DR –Inferior outcomes are seen in clinical stage III disease with failure to achieve a pCR and in clinically node-positive patients with persistently positive axillary LNs after NACT Results are consistent with the FDA-requested meta-analysis CALGB/Alliance 40603: Conclusions San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.

CALGB/Alliance 40603: Summary Our study was underpowered to determine whether the increases in the pCR rates seen with the addition of carboplatin and bevacizumab improve EFS or OS Previous studies (BEATRICE, E5103, GeparQuinto, NSABP B-40) have failed to demonstrate improvements in long-term outcomes (EFS, RFS or OS with the addition of bevacizumab to a control (neo)adjuvant chemotherapy regimen in stage I-III TNBC Results from other completed (GeparSixto) and ongoing (BrighTNess, NRG-003) studies in the neoadjuvant and adjuvant settings should help to clarify whether the addition of carboplatin benefits patients with early stage TNBC CALGB/Alliance 40603: Conclusions San Antonio Breast Cancer Symposium, December 8-12, 2015 This presentation is the intellectual property of the authors. Contact them at for permission to reprint and/or distribute.