Abstract GS01-02: Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2− breast cancer: KEYNOTE-756

Abstract Background: KEYNOTE-756 (NCT03725059) is a global phase 3 study of neoadjuvant pembrolizumab or placebo + chemotherapy followed by adjuvant pembrolizumab or placebo + endocrine therapy (ET) in patients with early-stage high-risk ER+/HER2– breast cancer. Here, we report primary pCR results and residual cancer burden (RCB) outcomes. Methods: Eligible patients 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 pembrolizumab 200 mg Q3W or placebo, both given with paclitaxel QW for 12 weeks, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant treatment). After definitive surgery (± radiation therapy), patients received pembrolizumab or placebo for 9 cycles + standard ET. Stratification factors include region (Eastern Europe, China, or Other), tumor PD-L1 status (CPS ≥1 [positive] vs CPS < 1 [negative]), nodal involvement (positive vs negative), 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. 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. Results: 1278 patients were randomized to pembrolizumab + chemotherapy (n=635) or placebo + chemotherapy (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, pembrolizumab + chemotherapy showed a statistically significant improvement in pCR (ypT0/Tis ypN0) vs placebo + chemotherapy: 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 pembrolizumab + chemotherapy on pCR was generally consistent in the prespecified subgroups. There were more patients with RCB-0 (24.7% vs. 15.6%) and RCB-1 (10.2% vs 8.1%) and fewer patients in the RCB-2 (40.8% vs. 45.3%) and RCB-3 categories (20.5% vs. 28.9%) in the pembrolizumab group versus the placebo group. In the neoadjuvant phase, grade ≥3 treatment-related AE rates were 52.5% with pembrolizumab + chemotherapy and 46.4% with placebo + chemotherapy, with 1 death in the pembrolizumab arm due to acute myocardial infarction. EFS results are still immature and continue to be evaluated. Conclusions: The addition of pembrolizumab to chemotherapy significantly increased the pCR rate and shifted RCB to lower residual disease categories in patients with early-stage high-risk ER+/HER2− breast cancer. Safety was consistent with the known profiles of each regimen. Citation Format: Fatima Cardoso, Joyce O'Shaughnessy, Heather McArthur, Peter Schmid, Javier Cortés, Nadia Harbeck, Melinda Telli, David Cescon, Peter A. Fasching, Zhimin Shao, Delphine Loirat, Yeon Hee Park, Manuel Gonzalez Fernandez, Gabor Rubovszky, Seock-Ah Im, Rina Hui, Toshimi Takano, Fabrice André, Hiroyuki Yasojima, Zhenzhen Liu, Yu Ding, Liyi Jia, Vassiliki Karantza, Konstantinos Tryfonidis, Aditya Bardia. Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2− breast cancer: KEYNOTE-756 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-02.