Abstract No. 
2017 San Antonio Breast Cancer Symposium
Dec 5-9

Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL

D Yee, A DeMichele, C Isaacs, F Symmans, C Yau, KS Albain, NM Hylton, A Forero-Torres, LJ van't Veer, J Perlmutter, HS Rugo, M Melisko, Y-Y Chen, R Balassanian, G Krings, B Datnow, F Hasteh, A Tipps, N Weidner, H Zhang, R Tickman, S Thornton, J Ritter, K Amin, M Klein, B Chen, G Keeney, T Ocal, M Feldman, N Klipfel, H Sattar, J Mueller, K Gwin, G Baker, B Kallakury, J Zeck, X Duan, C Ersahin, R Gamez, M Troxell, A Mansoor, L Grasso LeBeau, S Sams, J Wisell, S Wei, S Harada, T Vinh, MD Stamatakos, O Tawfik, F Fan, A Adams, M Rendi, S Minton, A Magliocco, S Sahoo, Y Fang, G Hirst, R Singhrao, SM Asare, AM Wallace, AJ Chien, ED Ellis, HS Han, AS Clark, JC Boughey, AD Elias, R Nanda, L Korde, R Murthy, J Lang, D Northfelt, Q Khan, KK Edmiston, R Viscusi, B Haley, K Kemmer, A Zelnak, DA Berry and LJ Esserman


Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014).

Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR.


We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p<0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype.


The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies.

Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all.

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