Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: results from the phase 1b open-label, multicohort KEYNOTE-173 study

Abstract

Background: The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC).

Patients and methods: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A-F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs).

Results: Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two 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%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%-71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively).

Conclusion: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels.

Trial registration: ClinicalTrials.gov identifier: NCT02622074.

Keywords: chemotherapy; immune checkpoint inhibitor; neoadjuvant therapy; pembrolizumab; programmed death ligand 1; triple-negative breast cancer.

Conflict of interest statement

Disclosure PS has received grants from AstraZeneca, Roche, Genentech, Oncogenex, Novartis, and 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 non-financial 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 Biotechnology, and 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 declared no conflicts of interest. LY, AW, KT, and VK are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

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