Neoadjuvant pembrolizumab or placebo + chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2– breast cancer: Results from the phase 3 KEYNOTE-756 study

Background: KEYNOTE‐756 (NCT03725059) is a global phase 3 study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo) followed by adjuvant pembro or pbo + endocrine therapy (ET) in patients (pts) with early‐stage high‐risk ER+ /HER2– breast cancer. We report primary pCR results and residual cancer burden (RCB) outcomes. Materials and Methods: Pts with T1c‐2 (≥2 cm) cN1‐2 or T3‐4 cN0‐2, centrally confirmed, grade 3, invasive ductal ER+/HER2− breast cancer were randomized 1:1 to receive neoadjuvant pembro 200 mg Q3W or pbo, both given with paclitaxel QW for 12 wk, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant treatment). After definitive surgery (± radiation therapy), pts received pembro or pbo for 9 cycles + standard ET. Stratification factors include region, tumor PD‐L1 status, nodal involvement, ER positivity, and anthracycline schedule. Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS. Secondary endpoints include OS, pCR defined as ypT0 ypN0 and ypT0/Tis, and safety. RCB was an exploratory endpoint and was assessed by a local pathologist at the time of surgery. RCB‐0, −1, −2, and −3 denote increasingly larger residual disease. An institutional review board at each site approved the protocol. Patients provided written informed consent. Results: 1278 pts were randomized to pembro + chemo (n = 635) or pbo + chemo (n = 643). At the final pCR analysis (May 25, 2023, first interim analysis data cutoff), median follow‐up was 33.2 mo (range, 9.7–51.8). In the ITT population, pembro + chemo showed a statistically significant improvement in pCR (ypT0/Tis ypN0) vs pbo + chemo: 24.3% (95% CI, 21.0–27.8) vs 15.6% (95% CI, 12.8–18.6); estimated difference, 8.5 percentage points (95% CI, 4.2–12.8); P = 0.00005; results were consistent for the secondary pCR definitions, ypT0 ypN0 (21.3% vs 12.8%) and ypT0/Tis (29.4% vs 18.2%). The benefit of pembro + chemo on pCR was generally consistent in the prespecified subgroups. There were more pts with RCB‐0 (24.7% vs. 15.6%) and RCB‐1 (10.2% vs 8.1%) and fewer pts in the RCB‐2 (40.8% vs. 45.3%) and RCB‐3 categories (20.5% vs. 28.9%) in the pembro group versus the pbo group. In the neoadjuvant phase, grade ≥3 treatment‐related AE rates were 52.5% with pembro + chemo and 46.4% with pbo + chemo, with 1 death in the pembro arm due to acute myocardial infarction. EFS results are immature and continue to be evaluated. Conclusion: Addition of pembro to chemo significantly increased the pCR rate and shifted RCB+ to lower residual disease categories in pts with early‐stage high‐risk ER /HER2− breast cancer. Safety was consistent with the known profiles of each regimen. Conflict of interest: Other Substantive Relationships: Fatima Cardoso: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi‐Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre‐Fabre, prIME Oncology, Roche, Sanofi, Samsung, Bioepis, Seagen, Teva, and Touchime. Support for attending meetings and/or travel from Pfizer, AstraZeneca, Roche, Gilead, and Seagen. Joyce O’ Shaughnessy: consultant: AbbVie, Amgen, AstraZeneca, Bristol‐Myers Squibb, Celgene, Daiichi Sankyo Company, Eisai, Eli Lilly and Company, F. Hoffmann‐La Roche, G1 Therapeutics, Genentech, Genomic Health, Heron Therapeutics, Inc., Ipsen Biopharmaceuticals, Inc, MSD, Novartis, Pfizer, Pierre Fabre Pharmaceuticals, Inc., Sanofi US Services Inc., Seattle Genetics. Heather McArthur reports receiving consultancy fees from Amgen, AstraZeneca, Bristol Myers Squibb, Calithera, Celgene, Crown Bioscience, Daiichi‐Sankyo, Eli Lilly, Genentech/Roche, Gilead, Immunomedics, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, OBI Pharma, Peregrine, Pfizer, Puma, Seattle Genetics, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, and TapImmune and research support from Bristol Myers Squibb, BTG, MedImmune LLC/AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Peter Schmid: grant/contract: Astellas Pharma, AstraZeneca, F. Hoffmann‐La Roche, Genentech, Medivation Inc., Novartis, OncoGenex Pharmaceuticals, Inc. consultant: AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, F. Hoffmann‐La Roche, MSD, Novartis, Pfizer, Puma Biotechnology data and safety monitoring: Novartis. Javier Cortes: Consulting Fees (e.g., advisory boards) Author Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead. Fees for Non‐CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) Author Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MSD, Daiichi Sankyo. Contracted Research Author Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman‐La Roche, Guardant Health, MSD, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds) Author MedSIR. Other Author Travel, accommodation: Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo. Nadia Harbeck: consultant: AstraZeneca, Daiichi‐Sankyo, F. Hoffmann‐La Roche, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer Pharma GmbH, Pierre Fabre Pharmaceuticals, Inc., Sandoz, Seagen Inc., West German Study Group other business ownership: West German Study Group other: Amgen, Exact Sciences, Lilly Deutschland, Pierre Fabre Pharmaceuticals, Inc. Melinda L Telli: Nothing to disclose. David W. Cescon: Consultancy/Advisory: AstraZeneca, Exact Sciences, Eisai, Gilead, GlaxoSmithKline, Inflex, Inivata/Neogenomics, Lilly, MSD, Novartis, Pfizer, Roche and SAGA research support to their institution from AstraZeneca, GlaxoSmithKline, Inivata, Knight, MSD, Pfizer, and Roche is a member of a trial steering committee for AstraZeneca, MSD, and GlaxoSmithKline and holds a patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. Peter A. Fasching: Daiichi‐Sankyo consultant: Agendia, AstraZeneca, Celgene, Clin‐Sol Research Gmbh, Gilead Sciences, Lilly Deutschland, Macrogenics, Merck Sharp & Dohme, Myelo Therapeutics, Pfizer Deutschland, Roche, Seagen Inc. grant/contract: Biontech, Cepheid. Zhimin Shao: Nothing to disclose. Delphine Loirat: Nothing to disclose. Yeon Hee Park: Consultancy or advisory fees: AstraZeneca, Eisai, Eli Lilly Export S.A. Puerto Rico Branch, Novartis, Pfizer, and Roche. Research funding: AstraZeneca, MSD, Novartis, Pfizer, and Roche. Manuel Gonzalez Fernandez: Nothing to disclose. Gábor Rubovszky: Honoraria from MSD, Roche, Novartis, Lilly, Swixx and Pfizer. Seock‐Ah Im: Consulting/Advisory role: AstraZeneca, Novartis, Roche/ Genentech, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Daiichi Sankyo, Idience Co. Ltd, and Bertis Research funding to institution: AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical, Eisai Korea, and Boryung Pharm. Rina Hui: consultant: AstraZeneca, Bristol‐Myers Squibb, Eisai, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, OncoSec Medical Incorporated, Pfizer Australia, Roche Products Pty Ltd, Seagen Inc. Toshimi Takano: Lecture fees from Daiichi‐Sankyo, Chugai, Kyowa Kirin, Eisai, Pfizer, Eli Lilly, and Celltrion. Research funding from Daiichi‐Sankyo, Chugai, Eisai, Ono, and MSD. Fabrice André: Research grants to institution: AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, and Roche. Hiroyuki Yasojima: Nothing to disclose. Zhenzhen Liu: Nothing to disclose. Yu Ding, Liyi Jia, Vassiliki Karantza, and Konstantinos Tryfonidis: employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholders in Merck & Co., Inc., Rahway, NJ, USA. Aditya Bardia: Consultant/Advisory board: Pfizer, Novartis, Genentech, Merck & Co., Inc., Rahway, NJ, USA, Radius Health, Immunomedics/Gilead, Sanofi, Daiichi Pharma/Astra Zeneca, Phillips, Eli Lilly, and Foundation Medicine. Contracted Research/Grant (to institution): Genentech, Novartis, Pfizer, Merck & Co., Inc., Rahway, NJ, USA, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/Astra Zeneca, and Eli Lilly.