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 40603 (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 wsikov@wihri.org for permission to reprint and/or distribute.

CALGB 40603: Schema – Randomized phase II

Paclitaxel 80 mg/m2 wkly x 12 ddAC x 4

Bevacizumab 10 mg/kg q2wks x 9

Bevacizumab 10 mg/kg q2wks x 9

Carboplatin AUC 6 q3wks x 4

Carboplatin AUC 6 q3wks x 4

Paclitaxel 80mg/m2 weekly x 12

Surgery&*

XRT*

No Adjuvant Systemic Treatment Planned*

Paclitaxel 80 mg/m2 wkly x 12

Paclitaxel 80 mg/m2 wkly x 12

Paclitaxel 80 mg/m2 wkly x 12

Research biopsies-

frozen and fixed

2 X 2 Randomization

ddAC x 4

ddAC x 4

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 wsikov@wihri.org 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 wsikov@wihri.org for permission to reprint or distribute.

CALGB 40603 – pCR Results by factor

pCR Breast ypT0/is (%, 95% CI) Overall Carbo No Carbo OR p-value

53 (49-58)60 (54-66) 46 (40-53) 1.76 0.0018

Bev No Bev OR p-value 59 (52-65) 48 (41-54) 1.58 0.0089

pCR Breast/Axilla ypT0/is ypN0 (%, 95% CI) Overall Carbo No Carbo OR p-value

48 (43-53) 54 (48-61) 41 (35-48) 1.71 0.0029

Bev No Bev OR p-value 52 (45-58) 44 (38-51) 1.29 0.0570

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 40603 – 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 wsikov@wihri.org for permission to reprint and/or distribute.

CALGB 40603 – 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 wsikov@wihri.org for permission to reprint and/or distribute.

pCR Breast pCR Breast/Axilla

pCR Breast/Axilla

or RCB I*

Yes/No N (%) 231 (52%)/212 (48%)

207 (47%)/236 (53%)

266 (60%)/177 (40%)

EFS-HR 0.33 (0.22-0.50) 0.30 (0.19-0.46) 0.29 (0.20-0.43)

OS-HR 0.28 (0.17-0.46) 0.20 (0.11-0.36) 0.21 (0.13-0.34)

CALGB 40603 – 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 wsikov@wihri.org for permission to reprint and/or distribute.

CALGB 40603 – 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 wsikov@wihri.org for permission to reprint and/or distribute.

CALGB 40603 – 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 wsikov@wihri.org 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 wsikov@wihri.org for permission to reprint and/or distribute.

From meta-analysis; CALGB 40603 superimposed

pCR rates 47.8% (40603)vs. 33.6% (meta-analysis)

CALGB 40603 – 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 wsikov@wihri.org for permission to reprint and/or distribute.

Carboplatin Bevacizumab

Yes No Yes No

EFS3-year 76% 71% 75% 72%

HR 0.84 (0.58-1.22) 0.80 (0.55-1.17)

OS3-year 81% 85% 85% 81%

HR 1.15 (0.74-1.79) 0.76 (0.49-1.19)

CALGB 40603 – 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 wsikov@wihri.org for permission to reprint and/or distribute.

CALGB 40603 – 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 wsikov@wihri.org for permission to reprint and/or distribute.

CALGB 40603 – 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 wsikov@wihri.org 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 wsikov@wihri.org for permission to reprint and/or distribute.

Event type OverallFactor

Carbo No Carbo Bev No Bev

Patients 443 225 218 222 221EFS Events 109 52 57 50 59 Ipsilateral Inv Br Rec 36 14 22 13 23 Other LRR 18 7 11 8 10 Distant Recurrence 80 40 40 40 40OS Events 79 43 36 35 44 Breast Cancer Death 70 38 32 32 38 Non-BC, non-Rx Death 4 3 1 1 3 Unknown Death 5 2 3 2 3

CALGB 40603 – 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 wsikov@wihri.org 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 wsikov@wihri.org 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 wsikov@wihri.org for permission to reprint and/or distribute.