M Maio1, P A Ascierto2, L Manzyuk3, D Motola-Kuba4, N Penel5, P A Cassier6, G M Bariani7, A De Jesus Acosta8, T Doi9, F Longo10, W H Miller11, D-Y Oh12, M Gottfried13, L Xu14, F Jin14, K Norwood14, A Marabelle15. 1. University of Siena and Center for Immuno-Oncology, Department of Oncology, University Hospital, Siena, Italy. Electronic address: maio@unisi.it. 2. Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Pascale, Naples, Italy. 3. Outpatient Medical Treatment Department, NN Blokhin National Medical Research Center of Oncology, Moscow, Russia. 4. COMOP A.C., Clinical Investigation, Mexico City, Mexico. 5. Medical Oncology Department, Centre Oscar Lambret and Lille University, Lille, France. 6. Department of Medical Oncology, Centre Léon Bérard, Lyon, France. 7. Department of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil. 8. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA. 9. Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan. 10. Medical Oncology Department, Ramon y Cajal University Hospital, IRYCIS, CIBERONC, Madrid, Spain. 11. Segal Cancer Centre, Jewish General Hospital, Montréal, Canada; Department of Medicine, McGill University, Montréal, Canada. 12. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea. 13. Department of Medical Oncology, Meir Medical Center, Kfar Saba, Israel. 14. Merck & Co., Inc., Rahway, USA. 15. Department of Therapeutic Innovation and Early Trials, Gustave Roussy, Institut National de la Santé et de la Recherche Médicale U1015/CIC1428, Université Paris Saclay, Villejuif, France.
Abstract
BACKGROUND: Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODS: Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTS: Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONS: Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.
BACKGROUND: Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODS: Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTS: Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONS: Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.