P Schmid1, R Salgado2, Y H Park3, E Muñoz-Couselo4, S B Kim5, J Sohn6, S-A Im7, T Foukakis8, S Kuemmel9, R Dent10, L Yin11, A Wang11, K Tryfonidis11, V Karantza11, J Cortés12, S Loi2. 1. Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, UK. Electronic address: p.schmid@qmul.ac.uk. 2. Division of Research, Department of Oncology, Peter MacCallum Cancer Centre, Sir Peter MacCallum, University of Melbourne, Melbourne, Australia. 3. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 4. Department of Medical Oncology, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain. 5. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul. 6. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. 7. Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. 8. Department of Oncology-Pathology, Karolinska Institutet and Breast Cancer Center, Theme Cancer, Karolinska University Hospital, Solna, Sweden. 9. Interdisciplinary Breast Unit, Medical Oncology, Clinics Essen-Mitte, Essen, Germany. 10. Department of Medical Oncology, National Cancer Centre, Singapore. 11. Merck & Co., Inc., Kenilworth, USA. 12. Department of Medical Oncology, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain; IOB Institute of Oncology, Quiron Group, Barcelona, Spain.
Abstract
BACKGROUND: The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A-F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). RESULTS: Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%-71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). CONCLUSION: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02622074.
BACKGROUND: The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A-F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumorprogrammed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). RESULTS: Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%-71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). CONCLUSION: Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumorPD-L1 expression and sTIL levels. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02622074.
Authors: Julia Caroline Radosa; Lisa Stotz; Carolin Müller; Askin Canguel Kaya; Erich-Franz Solomayer; Marc Philipp Radosa Journal: Breast Care (Basel) Date: 2020-10-13 Impact factor: 2.860
Authors: Yun-Long Wang; Ming-Biao Wei; Wan-Wen Zhao; Li-Li Feng; Xin-Ke Yin; Shao-Mei Bai; Xiang-Bo Wan; Mien-Chie Hung; Andrew Z Zou; Michael H Wang; Jian Zheng; Caolitao Qin; Xin-Juan Fan Journal: Am J Cancer Res Date: 2021-05-15 Impact factor: 6.166
Authors: Leisha A Emens; Sylvia Adams; Ashley Cimino-Mathews; Mary L Disis; Margaret E Gatti-Mays; Alice Y Ho; Kevin Kalinsky; Heather L McArthur; Elizabeth A Mittendorf; Rita Nanda; David B Page; Hope S Rugo; Krista M Rubin; Hatem Soliman; Patricia A Spears; Sara M Tolaney; Jennifer K Litton Journal: J Immunother Cancer Date: 2021-08 Impact factor: 13.751
Authors: Clinton Yam; Er-Yen Yen; Jeffrey T Chang; Roland L Bassett; Gheath Alatrash; Haven Garber; Lei Huo; Fei Yang; Anne V Philips; Qing-Qing Ding; Bora Lim; Naoto T Ueno; Kasthuri Kannan; Xiangjie Sun; Baohua Sun; Edwin Roger Parra Cuentas; William Fraser Symmans; Jason B White; Elizabeth Ravenberg; Sahil Seth; Jennifer L Guerriero; Gaiane M Rauch; Senthil Damodaran; Jennifer K Litton; Jennifer A Wargo; Gabriel N Hortobagyi; Andrew Futreal; Ignacio I Wistuba; Ryan Sun; Stacy L Moulder; Elizabeth A Mittendorf Journal: Clin Cancer Res Date: 2021-10-01 Impact factor: 12.531