Pembrolizumab Plus Chemotherapy as Neoadjuvant Treatment for Locally Advanced Triple-Negative Breast Cancer: Results from the Phase 1b Open-Label, Multicohort KEYNOTE-173 Study

Abstract

Background: The phase 1b KEYNOTE-173 study assessed the safety and preliminary antitumour activity of neoadjuvant chemotherapy plus pembrolizumab in locally advanced non-metastatic triple-negative breast cancer (TNBC). Methods: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), followed by 8 cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks and then doxorubicin and cyclophosphamide for additional 12 weeks before surgery. Primary endpoints were safety and recommended phase 2 dose (RP2D); secondary endpoints were pathological complete response (pCR) rate, objective response rate (ORR), event-free and overall survival. Exploratory endpoints included the relationship between outcome and potential biomarkers, such as tumour programmed death ligand 1 (PD-L1) expression (combined positive score [CPS]) and stromal tumour-infiltrating lymphocyte levels (sTILs). Study is registered with ClinicalTrials.gov, NCT02622074. Findings: Sixty patients were enrolled between February 18, 2016 and February 28, 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n=9 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold, whereas 2 cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%), which were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range, 30%–80%). 12-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 CPS, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). Interpretation: The combination of neoadjuvant chemotherapy with pembrolizumab for locally advanced TNBC showed manageable toxicity and promising antitumour activity. In an exploratory analysis, pCR rate showed positive correlation with tumour PD-L1 expression and sTIL levels. Funding: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Declaration of Interest: PS has received grants from AstraZeneca, Roche, Genentech, Oncogenex, Novartis, Astellas and consulting fees from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, and Puma Biotechnology. His spouse has received consulting fees from Genentech and Roche. RS received research support for the scoring of sTILs presented in this manuscript. YHP has received grants, personal fees and non-financial support from Pfizer, Eisai, and Roche, personal fees and nonfinancial support from Merck, grants and personal fees from Novartis, personal fees from Celgene, and non-financial support from Hanmi. SBK has received grants from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc, and DongKook Pharm Co and has received consulting fees from Novartis, AstraZeneca, Lilly, Enzychem, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, and Daiichi-Sankyo. JS has received grants from Merck, Roche, Novartis, AstraZeneca, Lilly, Pfizer, Bayer, GlaxoSmithKline, CONTESSA, and Daiichi Sankyo. TF has received grants and consulting fees (as institutional payments) from Pfizer, grants from Roche, and royalties for authorship from Wolters Kluwer Health (UpToDate). SK has received personal fees from Roche, Genomic Health, Lilly, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, Merck, Pfizer, Puma Biotechnology, and PFM Medical and non-financial support from Roche and Daiichi Sankyo. RD has received personal fees from AstraZeneca, Eisai, Lilly, Merck, Novartis, Pfizer, Roche, and Seattle Genetics. JC has received grants (as institutional payments) from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck, Pfizer, Piqur Therapeutics, Puma Biotechnology, Queen Mary University of London, and Seagen, consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck, GlaxoSmithKline, and Leuko, and honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck, and Daiichi Sankyo. SL has received grants (as institutional payments) from Novartis, Bristol-Myers Squibb, Merck, Roche-Genentech, Puma Biotechnologyand Eli Lilly, has acted as a consultant (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech and has received consulting fees (to institution) from Aduro Biotech. EMC has nothing to disclose. LY, AW, KT, and VK are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Ethical Approval: The study protocol was approved by the appropriate institutional review board or independent ethics committee at each participating institution. The study was conducted in accordance with the protocol, good clinical practice guidelines, provisions of the Declaration of Helsinki and all local regulations. All patients provided written informed consent to participate.