LBA21 - KEYNOTE-756: Phase III study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER+/HER2– breast cancer

Background

KEYNOTE-756 (NCT03725059) is a global phase 3 study of neoadjuvant pembro or pbo + chemo followed by adjuvant pembro or pbo + ET in patients (pts) with early-stage high-risk ER⁺/HER2^– breast cancer. Here, we report primary pCR results.

Methods

Eligible 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 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 (Eastern Europe, China, or Other), tumor PD-L1 status (CPS ≥1 [+] vs CPS <1 [–]), nodal involvement (+ vs –), ER positivity (≥10% vs <10%) and anthracycline schedule (Q3W vs Q2W). Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS. Secondary endpoints include OS, pCR defined as ypT0 ypN0 and ypT0/Tis and safety.

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. 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 still immature and continue to be evaluated.

Conclusions

The addition of pembro to chemo significantly increased the pCR rate in pts with early-stage high-risk ER⁺/HER2^– breast cancer. Safety was consistent with the known profiles of each regimen.

Clinical trial identification

EudraCT 2017-004869-27, NCT03725059.

Editorial acknowledgement

Editorial assistance in the writing of the abstract was provided by Christine McCrary Sisk, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Disclosure

F. Cardoso: Financial Interests, Personal, Other, Consultancy: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GSK, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Prime Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva; Financial Interests, Personal, Advisory Board: Gilead, Iqvia, Touchime; Financial Interests, Institutional, Local PI: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Bayer, Daiichi Sankyo, Eisai, Fresenius GmbH, Genentech, GSK, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Taiho Oncology, Tesaro, Tigris, Wilex, Wyeth, Gilead; Non-Financial Interests, Leadership Role, President: ABC Global Alliance and ABC Consensus Conference and Guidelines; Non-Financial Interests, Member: ESMO, ESO, EORTC, BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC. H.L. McArthur: Financial Interests, Personal, Advisory Board: Lilly, Pfizer, Immunomedics, Merck, Seattle Genetics, Daiichi Sankyo, Bristol Myers Squibb, AstraZeneca, Puma Biotechnology, Gilead, Crown Bioscience; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MedImmune, AstraZeneca, Merck. P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Gilead, Eisai, MSD, Seagen, Amgen, Celgene, Lilly; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Jazz Pharmaceuticals, AbbVie, Scorpion Therapeutics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MAJ3 Capital; Financial Interests, Personal, Stocks/Shares, (relative): Leuko; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant Health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca, Steamline Therapeutics; Other, travel cost and expenses: Merck Sharp&Dhome. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Art Tempi, Onkowissen, Medscape, Gilead, Sanofi, Zuelligpharma, Viatris; Financial Interests, Personal, Other, IDMC: Roche; Financial Interests, Personal, Advisory Board: Sandoz-Hexal, Seagen, Aptitude Health, Pfizer, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Palleos, Seagen, TRIO, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. M.L. Telli: Financial Interests, Institutional, Research Grant: Arvinas, AbbVie, Bayer, EMD Serono, Genentech/Roche, GSK, Hummingbird Biosciences, Merck, Novartis, OncoSec, Pfizer; Non-Financial Interests, Personal and Institutional, Principal Investigator: OncoSec, GSK; Financial Interests, Personal, Advisory Role: AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Genentech/Roche, G1 Therapeutics, Gilead, GSK, Guardant, Immunomedics, Lilly, Merck, Natera, Novartis, Pfizer, RefleXion, Replicate, Sanofi. D.W. Cescon: Financial Interests, Personal and Institutional, Funding: Merck & Co., Inc.; Financial Interests, Institutional, Research Grant: AstraZeneca, Guardant Health, Gilead, GSK, Inivata/NeoGenomics, Knight, Merck, Pfizer, Roche; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Exact Sciences, Eisai, Gilead, GSK, Inflex, Inivata/Neogenomics, Merck, Novartis, Pfizer, Roche, Saga; Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, GSK; Financial Interests, Personal, Stocks/Shares: INFLEX; Financial Interests, Personal, Other, 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: 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. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Ondonate, Pfizer, Puma, Prime Oncology, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi. P. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, AstraZeneca, Merck, Sharp & Dohme, Gilead, Lilly, Seagen; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Local PI: BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v.. D. Loirat: Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, Pfizer, novartis, ExactSciences; Financial Interests, Personal, Other, Travel/congress: MSD; Financial Interests, Personal, Other, Travel/Congress: Roche, AstraZeneca, Gilead, Novartis; Financial Interests, Personal, Invited Speaker: Gilead, Lilly; Financial Interests, Personal, Other, Travel/Congres: Pflizer. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pfizer, Roche, MSD; Non-Financial Interests, Principal Investigator: AstraZeneca, Lilly, Pfizer, Novartis, MSD, Roche, Daiichi Sankyo; Financial Interests, Institutional, Writing Engagement: Pfizer. Y. Ding: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. L. Jia: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. V.V. Karantza: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. K.E. Tryfonidis: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisai, Lilly, Mersana, AstraZeneca/Daiichi Sankyo, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Coordinating PI: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.; Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi Sankyo, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. All other authors have declared no conflicts of interest.