washington; seattle; swedish cancer; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Female; Humans; Neoadjuvant Therapy; Neoplasm Staging; Programmed Cell Death 1 Receptor
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.
Nanda, Rita; Liu, Minetta C; Yau, Christina; Shatsky, Rebecca; Pusztai, Lajos; Wallace, Anne; Chien, A Jo; Forero-Torres, Andres; Ellis, Erin D; Han, Heather; Clark, Amy; Albain, Kathy; Boughey, Judy C; Jaskowiak, Nora T; Elias, Anthony; Isaacs, Claudine; Kemmer, Kathleen; Helsten, Teresa; Majure, Melanie; Stringer-Reasor, Erica; Parker, Catherine; Lee, Marie C; Haddad, Tufia; Cohen, Ronald N; Asare, Smita; Wilson, Amy; Hirst, Gillian L; Singhrao, Ruby; Steeg, Katherine; Asare, Adam; Matthews, Jeffrey B; Berry, Scott; Sanil, Ashish; Schwab, Richard; Symmans, W Fraser; van 't Veer, Laura; Yee, Douglas; DeMichele, Angela; Hylton, Nola M; Melisko, Michelle; Perlmutter, Jane; Rugo, Hope S; Berry, Donald A; and Esserman, Laura J, "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." (2020). Articles, Abstracts, and Reports. 4328.