A phase II study of nivolumab and ipilimumab with radiation therapy in patients with metastatic, microsatellite stable colorectal cancer.
Authors: Koenig Julie L. , Pappas Leon , Yeap Beow Y. , Clark Jeffrey William , Klempner Samuel J , Ryan David P. , Allen Jill N. , Blaszkowsky Lawrence Scott , Giantonio Bruce J. , Perez Kimberly , Schlechter Benjamin L. , Wo Jennifer Yon-Li , Roberts Hannah Johnson , Meyerhardt Jeffrey A. , Ludes Sydney D. , Zecca Katharine , Drapek Lorraine C. , Mehta Arnav , Hong Theodore S. , Parikh Aparna Raj 
Published: June 2023

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Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Radiation therapy (RT) may increase the response rate to ICIs through multiple mechanisms. In our phase 2 trial (NCT03104439), 40 patients with metastatic MSS CRC were enrolled to receive ipilimumab and nivolumab with RT (24 Gy/3 fractions) starting on C2D1. Among the 27 patients who received RT (33% dropout rate), the disease control rate (DCR) was 37% and objective response rate (ORR) was 15%. To confirm this signal and address dropout prior to RT, we conducted a phase 2 study of nivolumab and ipilimumab with RT moved to C1D1. Methods: In this open-label, single-arm, phase 2 study (NCT04361162), eligible patients had histologically confirmed metastatic MSS CRC, ECOG PS 0-1, and progressed on at least one line of chemotherapy. Treatment consisted of ipilimumab 1 mg/kg every 6 weeks for the first 4 cycles, nivolumab 240 mg every 2 weeks on a 6-week cycle, and RT with 24 Gy/3 fractions to one site starting on C1D1. Treatment continued until disease progression, discontinuation, or withdrawal. The primary endpoint was ORR outside of the RT field by RECIST 1.1 with radiological evaluations every 3 months. The treatment regimen was considered to have promising activity if at least 3 of 30 patients achieved an objective response in unirradiated lesions. Secondary endpoints included DCR, PFS, OS, and safety. A single-stage design was used to enroll 30 patients for intention-to-treat analysis of patients receiving at least one dose of study treatment. The per protocol analysis included patients who completed C1D1. The treatment regimen was considered to have promising activity if at least 3 of 30 patients achieved an objective response in unirradiated lesions, providing 85% power to reject 4% ORR in favor of 15% ORR at a significance level of 15%. Results: We enrolled and treated 30 patients (median age 56 years [range 28-85], 60% male, 83% white) from 10/2020 to 05/2022. Patients received a median of 2 (range, 1-7) prior lines of chemotherapy. All patients in the intention-to-treat population also met criteria for inclusion in the per protocol analysis. The ORR was 13% (4/30; 95% CI, 4-31%), DCR was 33% (10/30; 95% CI, 17-53%), median PFS was 2.4 months (95% CI, 1.8-2.9 months), and median OS was 10.6 months (95% CI, 6.8-17.8 months). 16 patients had grade 3+ treatment-related serious adverse events, including lymphopenia (3 patients with grade 4), anemia, diarrhea, colitis, vomiting, alkaline phosphatase increase, hypothyroidism, fatigue, and myositis. Conclusions: Treatment with ipilimumab, nivolumab, and RT starting on C1D1 showed promising activity in patients with traditionally immunoresistant metastatic MSS CRC. Further analyses are ongoing to evaluate optimal patient selection and radiation strategies. Clinical trial information: NCT04361162 .