Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women with Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial

Rita Nanda, Minetta C. Liu, Christina Yau, Rebecca Shatsky, Lajos Pusztai, Anne Wallace, A. Jo Chien, Andres Forero-Torres, Erin Ellis, Heather Han, Amy Clark, Kathy Albain, Judy C. Boughey, Nora T. Jaskowiak, Anthony Elias, Claudine Isaacs, Kathleen Kemmer, Teresa Helsten, Melanie Majure, Erica Stringer-ReasorCatherine Parker, Marie C. Lee, Tufia Haddad, Ronald N. Cohen, Smita Asare, Amy Wilson, Gillian L. Hirst, Ruby Singhrao, Katherine Steeg, Adam Asare, Jeffrey B. Matthews, Scott Berry, Ashish Sanil, Richard Schwab, W. Fraser Symmans, Laura Van 'T Veer, Douglas Yee, Angela Demichele, Nola M. Hylton, Michelle Melisko, Jane Perlmutter, Hope S. Rugo, Donald A. Berry, Laura J. Esserman

Research output: Contribution to journalArticlepeer-review

416 Scopus citations


Importance: Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed. Objective: To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. Design, Setting, and Participants: The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016. Interventions: Participants were randomized to receive taxane-and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. Main Outcomes and Measures: The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. Results: Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-Term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up). Conclusions and Relevance: When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.

Original languageEnglish (US)
Pages (from-to)676-684
Number of pages9
JournalJAMA Oncology
Issue number5
StatePublished - May 2020

Bibliographical note

Publisher Copyright:
© 2020 American Medical Association. All rights reserved.


Dive into the research topics of 'Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women with Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial'. Together they form a unique fingerprint.

Cite this