KEYNOTE-756: Randomized, double-blind, phase III study of pembrolizumab vs placebo + neoadjuvant chemotherapy (CT) and adjuvant endocrine therapy (ET) for high-risk, early-stage estrogen receptor–positive human epidermal growth factor receptor 2–negative (ER+/HER2−) breast cancer (BC)
Authors: F. Cardoso, L. Jia, K. Hirshfield, V. Karantza
Journal: Annals of Oncology (2019)

Background: Although ER+/HER2− BC has better overall prognosis than other subtypes, a high-risk subpopulation is characterized by high-grade tumors, decreased sensitivity to ET, higher responsiveness to CT, and worse prognosis. A meta-analysis of prospective studies on neoadjuvant chemotherapy (NAC) to treat stage I to III BC showed that increased pathologic complete response (pCR) rates at surgery were associated with improved survival in triple-negative BC, HER2+ BC, and high-grade HR+/HER2− BC. Patients with vs without pCR after NAC for high-grade HR+/HER2− BC had a 90% vs 60% 5-year event-free survival (EFS) rate, respectively. Thus, increased pCR rates after NAC may have a substantial impact on the survival of 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 (pembro; vs placebo) + NAC followed by pembro (vs placebo) plus ET as adjuvant treatment for patients with high-risk, early-stage ER+/HER2− BC. Trial design: Patients with cT1c-2 cN1-2 (tumor size ≥2 cm) or cT3-4 cN0-2 grade 3, invasive, ductal ER+/HER2− BC will be stratified by lymph node involvement (pos vs neg), tumor PD-L1 status (pos vs neg), ER positivity (≥10% vs < 10%), and anthracycline dosing schedule (every 3 weeks [Q3W] vs Q2W), then randomized 1:1 to neoadjuvant treatment with pembro 200 mg Q3W or placebo combined with paclitaxel (80 mg/m2 Q1W) for 4 cycles followed by doxorubicin (60 mg/m2) or epirubicin (100 mg/m2), each with cyclophosphamide (600 mg/m2), Q2/3W for 4 cycles. After definitive surgery (± radiation therapy, as indicated), patients will receive adjuvant treatment of pembro (200 mg Q3W) or placebo for 9 more cycles combined with ET, which can be given for up to 10 years. Coprimary endpoints are pCR rate (ypT0/Tis ypN0) and EFS. Secondary endpoints include pCR rates (ypT0 ypN0 or ypT0/Tis, and using all 3 definitions in the PDL1+ subpopulation), overall survival, and safety. Enrollment is currently ongoing. Editorial acknowledgement: Rajni Parthasarathy, PhD, and Diane Neer, ELS, MedThink SciCom. Clinical trial identification: NCT03725059. Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure: F. Cardoso: Consulting: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Seattle Genetics, Teva. L. Jia, K. Hirshfield, V. Karantza: Employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may hold stock/stock options in Merck & Co., Inc., Kenilworth, NJ, USA.