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.
Bibliographical noteFunding Information:
Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics outside the submitted work; and personal fees from Aduro, AstraZeneca, Athenex, Celgene, Daiichi Sankyo, G1 Therapeutics, Genentech, MacroGenics, Merck, Novartis, Pfizer, Puma, and Syndax. Dr Liu reported nonfinancial support from Celgene, Merck, and Pfizer outside the submitted work. Dr Yau reported grants from the National Institutes of Health (NIH) during the conduct of the study; personal fees from NantOmics LLC outside the submitted work. Dr Pusztai reported grants and personal fees from Merck during the conduct of the study; personal fees from Genentech, personal fees from Novartis, grants and personal fees from AstraZeneca, and grants and personal fees from Seattle Genetics outside the submitted work. Dr Han reported grants from Quantum Leap Healthcare Collaborative during the conduct of the study; personal fees from Lilly, grants from the Department of Defense, and institutional funding from AbbVie, from Bristol-Myers Squibb, Novartis, Tesaro, Prescient, Horizon, Marker, G1 Therapeutics, and Seattle Genetics outside the submitted work. Dr Clark reported grants from Novartis outside the submitted work. Dr Albain reported grants from Quantum Leap Healthcare during the conduct of the study; personal fees from Genentech/Roche, Genomic Health, Inc; and Pfizer; a passed chairmanship from Puma, and personal fees from Myriad outside the submitted work. Dr Boughey reported grants from Quantum Leap during the conduct of the study. Dr Elias reported grants from QuantumLeap during the conduct of the study; nonfinancial support from Astellas; and valued security holdings in Merck, Lilly, Abbott, Pfizer, Agilent, AbbVie, Amgen, BMS, Gilead, Allergan, Alexion, and Biogen; grants from Deciphera, and grants from Xencor outside the submitted work. Dr Isaacs reported personal fees from Genentech, AstraZeneca, Novartis, and Pfizer, grants from Tesaro, and personal fees from PUMA outside the submitted work; and NCI Cancer Center Support Grant Translational Breast Cancer Research Consortium, and grants from the Komen Foundation, and the Safeway Foundation. Dr Kemmer reported that her husband has received honoraria totaling between $5000 to $10 000 from Astellas Pharmaceutical in October of 2019; and consultant fees ($5000 to $10 000) for advisory committee from Merck in August of 2019. Dr Helsten reported grants from Synthon, Lilly, Novartis, Bayer, Merrimack, AbbVie, and Pfizer outside the submitted work. Dr Stringer-Reasor reported grants from Susan G Komen, the V foundation, personal fees from Mylan, and personal fees from Lilly outside the submitted work. Dr Lee reported personal fees from Provepharm, Elucent Medical, grants from National Cancer Institute, and Department of Defense outside the submitted work. Dr Haddad reported personal fees from TerSera and grants from Takeda Oncology outside the submitted work. Dr Cohen reported grants from Quantum Leap Healthcare Collaborative during the conduct of the study. Dr S. Asare reported grants from Merck Sharp & Dohme Corp during the conduct of the study; grants from Synta Pharmaceuticals, Plexxikon, Pfizer, Medivation, Daiichi Sankyo, nonfinancial support from Agendia, grants from Seattle Genetics, AstraZeneca, Amgen, and Dynavax Technologies outside the submitted work. Dr Sanil reported Ashish Sanil is an employee of Berry Consultants, LLC, a private consulting firm with multiple clients in the pharmaceutical and medical device industry. Dr Schwab reported grants from Quantum Leap Healthcare Collaborative during the conduct of the study; grants from Galena Biopharma, Puma Biotechnology, Optimer Pharmaceuticals, Alliance Foundation, and Celgene outside the submitted work; in addition, Dr Schwab had a patent to Procend, Inc, pending; and expert witness consulting for Puma Biotechnology; Scientific consulting and equity interest in Samumed LLC; and equity interest in Procend, Inc. Dr Symmans reported an interest in intellectual property licensed by Delphi Diagnostics, security holdings in IONIS Pharmaceuticals, and personal fees and nonfinancial support from Merck outside the submitted work; in addition, Dr Symmans had a patent to 7 711 494 issued. Dr van 't Veer reported part-time employment and security holdings from Agendia NV outside the submitted work. Dr Yee reported grants from National Cancer Institute during the conduct of the study; personal fees from Apogen Biotechnology, Martell Diagnostic Laboratories, and Tempus, grants from Boehringer Ingelheim, and nonfinancial support from Akston Biosciences outside the submitted work. Dr Melisko reported institutional grants related to clinical trials from Lilly, Novartis, Nektar, KCRN Research, Puma, and AstraZeneca, and personal fees from Agendia outside the submitted work. Dr Rugo reported grants from Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi, Eisai, Seattle Genetics, Macrogenics, and Immunomedics, as well as travel support to attend meetings from Daiichi, Mylan, Pfizer, Amgen, Merck, AstraZeneca, Macrogenics, and Puma during the conduct of the study. Dr D. Berry reported personal fees from Berry Consultants, LLC, outside the submitted work. Dr Esserman sits on the board of directors of, and received grant funding from the study sponsor, Quantum Leap Healthcare Collaborative during the conduct of the study; and membership on the Blue Cross/Blue Shield Medical Advisory Committee. No other disclosures were reported.
Funding/Support: Supported by Quantum Leap
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PubMed: MeSH publication types
- Clinical Trial, Phase II
- Journal Article
- Multicenter Study
- Randomized Controlled Trial