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Original Investigation
February 13, 2020

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

Author Affiliations
  • 1The University of Chicago, Chicago, Illinois
  • 2Mayo Clinic, Rochester, Minnesota
  • 3University of California, San Francisco
  • 4University of California, San Diego
  • 5Yale University, New Haven, Connecticut
  • 6University of Alabama, Birmingham
  • 7Swedish Cancer Center
  • 8Moffitt Cancer Center, Tampa, Florida
  • 9University of Pennsylvania, Philadelphia
  • 10Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
  • 11University of Colorado, Aurora
  • 12Georgetown University, Washington, DC
  • 13Oregon Health & Science University, Portland
  • 14Quantum Leap Healthcare Collaborative, San Francisco, California
  • 15Berry Consultants, LLC
  • 16MD Anderson Cancer Center, Houston, Texas
  • 17University of Minnesota, Minneapolis
  • 18Gemini Group, Ann Arbor, Michigan
JAMA Oncol. 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650
Key Points

Question  Does the addition of the immune checkpoint inhibitor pembrolizumab to standard neoadjuvant chemotherapy improve efficacy in early-stage, high-risk, ERBB2 (formerly HER2)-negative breast cancer?

Findings  In this analysis of the adaptively randomized phase 2 I-SPY2 trial, including 250 women with early-stage breast cancer, the addition of pembrolizumab to standard neoadjuvant chemotherapy more than doubled complete pathologic response rates compared with chemotherapy alone for both hormone receptor-positive/ERBB2-negative, and triple-negative breast cancer.

Meaning  These results from the I-SPY2 trial suggest that there is a greater than 99% predictive probability that pembrolizumab plus neoadjuvant chemotherapy will be significantly better than chemotherapy alone in a phase 3 randomized clinical trial in ERBB2-negative breast cancer.


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

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