Singhrao, Ruby

Abstract Background: Pembrolizumab (P), an anti-PD-1 immune checkpoint inhibitor, has been approved for treatment of microsatellite instability-high and mismatch repair deficient cancers. In I-SPY 2, patients were randomized to receive standard chemotherapy alone or in combination with an experimental agent. P was one of the experimental agents evaluated in HER2- patients in I-SPY 2 and graduated in the TN, HR+HER2-, and HER2- signatures. We hypothesize that a combination of two signatures predicting response to veliparib/carboplatin therapy in I-SPY 2 [MammaPrint High2 (MP2)/PARPi7-high] and reflecting DNA damage repair deficiency, may also predict response to P. In addition, we also tested 9 gene expression signatures reflecting different aspects of DNA damage and repair: FA, MMR, BER, HR, TLS, NER, NHEJ, DR, and DNA damage sensing (DDS) pathways. Methods: Data from 249 patients (P: 69 and controls: 180) were available. Pre-treatment biopsies were assayed using Agilent gene expression arrays. All I-SPY 2 qualifying biomarker analyses follow a pre-specified analysis plan. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of P response if it associates with response in the P arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p<0.05). This analysis is also performed adjusting for HR status as a covariate, and within receptor subsets, sample size permitting. For successful biomarkers, we use Bayesian modeling to estimate the pCR rates of 'predicted sensitive' patients in each arm. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. Results: MP2 status associates with pCR in P (OR=7.7; p=0.00021), but also to a lesser extent in the control arm (OR=2.4:p=0.045), with an OR ratio of 3.3 which trends toward significance, even after adjusting for HR status (LR p=0.083). A majority of TN patients are MP2; and TN/MP2 patients have an estimated pCR rate of 67% in P (vs. 23% in control). Although only ~30% of HR+HER2- patients were MP2, their estimated pCR rate in P is 61%, compared to 29% in unselected HR+/HER2- patients. PARPi7 predicted response in the P arm only in the HR+HER2- group (LR p= 0.025), but not in the population as a whole or the TN subtype. Combining MP2 and PARPi7 into MP2/PARPi7-high did not improve performance over MP2 as a single biomarker. Of the 9 DDR pathway signatures tested, both BER and DDS associate with pCR in P, but only DDS (which includes ATM, ATR, CHEK1-2) associates with pCR in the P arm (LR p=0.00029), and not the control arm (LR p=0.53), with a significant interaction with treatment (LR p=0.0064) that retains significance in a model adjusting for HR status. When dichotomized to optimize the biomarker x treatment interaction, the estimated pCR rate is 75% in P vs 18% in control, in the DDS+ subset. Conclusion: In this small study, MP2 status and a DNA damage sensing pathway but not the PARPi7 or other repair pathways show promise as predictive biomarkers for immune checkpoint inhibition therapy in breast cancer. Citation Format: Yau C, Wolf D, Brown-Swigart L, Hirst G, Sanil A, Singhrao R, I-SPY 2 TRIAL Investigators, Asare S, DeMichele A, Berry D, Esserman L, van 't Veer L, Nanda R, Liu M, Yee D. Analysis of DNA repair deficiency biomarkers as predictors of response to the PD1 inhibitor pembrolizumab: Results from the neoadjuvant I-SPY 2 trial for stage II-III high-risk breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-14.

Abstract Background: 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. Results: 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. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: 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. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-08.