KEYNOTE-756: Randomized, double-blind, phase 3 study of pembrolizumab vs placebo combined with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage estrogen receptor–positive, human epidermal growth factor receptor 2–negative (ER+/HER2−) breast cancer.

person Fatima Cardoso Champalimaud Clinical Center/Champalimaud Foundation, Breast Unit, Lisbon, Portugal info_outline Fatima Cardoso, Aditya Bardia, Fabrice Andre, David W. Cescon, Heather L. McArthur, Melinda L. Telli, Sherene Loi, Javier Cortes, Peter Schmid, Nadia Harbeck, Carsten Denkert, Christian Jackisch, Liyi Jia, Kim M. Hirshfield, Vassiliki Karantza

Authors person Fatima Cardoso Champalimaud Clinical Center/Champalimaud Foundation, Breast Unit, Lisbon, Portugal info_outline Fatima Cardoso, Aditya Bardia, Fabrice Andre, David W. Cescon, Heather L. McArthur, Melinda L. Telli, Sherene Loi, Javier Cortes, Peter Schmid, Nadia Harbeck, Carsten Denkert, Christian Jackisch, Liyi Jia, Kim M. Hirshfield, Vassiliki Karantza Organizations Champalimaud Clinical Center/Champalimaud Foundation, Breast Unit, Lisbon, Portugal, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, Faculté de Medicine Paris-Sud XI, Gustave Roussy, Villejuif, France, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, Cedars-Sinai Medical Center, Los Angeles, CA, Stanford University School of Medicine, Stanford, CA, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia, Breast Cancer Program, Ramon y Cajal University Hospital, Madrid, Spain, Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, United Kingdom, Ludwig-Maximilian University of Munich, Munich, Germany, Institute of Pathology, Charité–Universitätsmedizin Berlin, Berlin, Germany, Sana Klinikum, Offenbach, Germany, Merck & Co., Inc., Kenilworth, NJ Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Although ER+/HER2− breast cancer (BC) has better overall prognosis than other subtypes, a high-risk subpopulation is characterized by high-grade tumors, decreased sensitivity to endocrine therapy (ET), higher responsiveness to chemotherapy (CT), and worse prognosis. Based on prior studies, increased pathological complete response (pCR) rates after neoadjuvant CT may have a substantial impact for patients with high-risk, early-stage HR+/HER2− BC. KEYNOTE-756 (ClinicalTrials.gov, NCT03725059) is a global, randomized, double-blind, phase 3 study of pembrolizumab (vs placebo) + CT as neoadjuvant treatment followed by pembrolizumab (vs placebo) + ET as adjuvant treatment for patients with high-risk, early-stage ER+/HER2− BC. Methods: Patients with T1c-2 cN1-2 (tumor size ≥2 cm) or T3-4 cN0-2 grade 3, invasive, ductal ER+/HER2− BC will be stratified by lymph node involvement (positive vs negative), tumor PD-L1 status (positive [CPS≥1] vs negative [CPS < 1]), ER positivity (ER+ ≥10% vs ER+ < 10%), and anthracycline dosing schedule (every 3 weeks [Q3W] vs Q2W), then randomized 1:1 to neoadjuvant treatment with pembrolizumab 200 mg Q3W or placebo combined with paclitaxel (80 mg/m 2 Q1W) for 4 cycles followed by doxorubicin (60 mg/m 2 ) or epirubicin (100 mg/m 2 ), each with cyclophosphamide (600 mg/m 2 ) Q2/3W for 4 cycles. After definitive surgery (± radiation therapy, as indicated), patients will receive adjuvant treatment of pembrolizumab (200 mg Q3W) or placebo for 9 more administrations combined with ET, which can be given for up to 10 years. There will be no crossover between treatment arms when moving from neoadjuvant to adjuvant treatment. Dual primary endpoints are pCR rate (ypT0/Tis ypN0) and event-free survival (EFS). Secondary endpoints include ypT0/Tis and ypT0 ypN0 pCR rates in all patients and all 3 pCR definitions in those with PD-L1+ tumors, EFS in patients with PD-L1+ tumors, overall survival, safety, and health-related quality of life. Interim analyses are planned. Enrollment is currently ongoing. Clinical trial information: NCT03725059