{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:53:42Z","timestamp":1793055222310,"version":"4.5.0"},"reference-count":28,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2023,5,1]]},"abstract":"Importance<\/jats:title>Immunotherapy combinations with activity in patients with microsatellite stable (MSS) metastatic colorectal cancer need to be identified.<\/jats:p><\/jats:sec>Objective<\/jats:title>To determine the recommended phase 2 dose (RP2D) of regorafenib, ipilimumab, and nivolumab (RIN) and evaluate its activity in an expansion cohort of patients with MSS metastatic colorectal cancer.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This nonrandomized clinical trial was a single-center 3\u2009+\u20093 dose de-escalation study with an effectiveness expansion cohort at the RP2D. After the identification of the RP2D, a study amendment was executed to explore a regorafenib dose optimization strategy to mitigate skin-related toxic effects. Study enrollment occurred between May 12, 2020, and January 21, 2022. The trial was conducted at a single academic center. A total of 39 patients with MSS metastatic colorectal cancer whose disease progressed after standard chemotherapy and who had not received prior regorafenib or anti\u2013programmed cell death protein 1 therapy were included.<\/jats:p><\/jats:sec>Interventions<\/jats:title>Patients received regorafenib daily for 21 days every 4 weeks; fixed-dose ipilimumab, 1 mg\/kg, intravenously every 6 weeks; and fixed-dose nivolumab, 240 mg intravenously every 2 weeks. Patients were treated until progression, unacceptable toxic effects, or completion of 2 years of therapy.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The primary end point was RP2D selection. Secondary end points were safety and overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours at the RP2D level.<\/jats:p><\/jats:sec>Results<\/jats:title>A total of 39 patients were enrolled, 23 (59.0%) were female, median age was 54 years (range, 25-75 years), 3 were Black (7.7%), and 26 were White (66.7%). No dose-limiting toxic effects were noted in the first 9 patients at the starting dose of RIN, with regorafenib dosed at 80 mg daily. No dose de-escalation was needed. This dose was declared the RP2D. Twenty more patients were enrolled at this level. The ORR, median progression-free survival (PFS), and overall survival (OS) in the RP2D cohort were 27.6%, 4 months (IQR, 2-9 months), and 20 months (IQR, 7 months to not estimable), respectively. For the 22 patients without liver metastases, the ORR, PFS, and OS were 36.4%, 5 months (IQR, 2-11), and greater than 22 months, respectively. A dose optimization cohort with regorafenib at 40 mg\/d on cycle 1 and 80 mg\/d on cycle 2 and beyond was associated with lower skin and immune toxic effects but had limited activity with stable disease for 5 of 10 patients as the best response.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>Results of this nonrandomized clinical trial suggest that RIN at the RP2D demonstrated interesting clinical activity in patients with advanced MSS colorectal cancer without liver metastases. 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