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

• Published in: JAMA oncology Vol. 6; no. 5; p. 676
• Main Authors: Nanda, Rita, Liu, Minetta C, Yau, Christina, Shatsky, Rebecca, Pusztai, Lajos, Wallace, Anne, Chien, A Jo, Forero-Torres, Andres, Ellis, Erin, 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, Esserman, Laura J
• Format: Journal Article
• Language: English
• Published: United States 01-05-2020
• Subjects: Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Female; Humans; Neoadjuvant Therapy - methods; Neoplasm Staging; Programmed Cell Death 1 Receptor - therapeutic use
• ISSN: 2374-2445
• DOI: 10.1001/jamaoncol.2019.6650

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.
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.
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.
Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery.
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.
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).
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.
ClinicalTrials.gov Identifier: NCT01042379.