Nivolumab and Ipilimumab in Advanced Mismatch Repair-Deficient/Microsatellite Instability-High Noncolorectal Cancers: A Nonrandomized Clinical Trial

Carlino MS, Gao B, Michael M, Marshall H, Gunjur A, Chan H, Zielinski R, So J, Harris SJ, Kee D, Collins IM, Lam WS, Lyle M, Underhill C, Brown MP, Harrup R, Wong SF, Grady J, Ballinger M, Tavancheh E, Thomas DM, Palmer J, Wilkie K, Cebon J, Klein O. JAMA Oncol. 2026 Jan 1;12(1):39-47. doi: 10.1001/jamaoncol.2025.4721. PMID: 41231502; PMCID: PMC12616531. TOP 10%

Abstract

Importance: Mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) cancers constitute one of the most immunogenic tumors. Anti-programmed cell death 1 (PD-1) monotherapy provides durable responses in a third of patients with advanced dMMR/MSI-H noncolorectal cancers. Combined anti-PD-1/cytotoxic lymphocyte antigen 4 (CTLA-4) blockade using nivolumab and ipilimumab has shown superiority to anti-PD-1 monotherapy in other immunogenic cancers such as metastatic melanoma. The Combination Immunotherapy in Rare Cancers Under Investigation (MOST-CIRCUIT) is the first trial that investigated combined anti-PD-1/CTLA-4 blockade in advanced dMMR/MSI-H noncolorectal cancers.

Objective: To evaluate the efficacy and safety of combined anti-PD-1/CTLA-4 blockade using nivolumab and ipilimumab in advanced dMMR/MSI-H noncolorectal cancers.

Design, setting, and participants: The MOST-CIRCUIT prospective multicenter nonrandomized phase 2 clinical trial enrolled 52 patients with advanced dMMR/MSI-H into cohort D. Patients were enrolled from August 2021 to February 2024 across 17 Australian and New Zealand sites. The analysis itself took place in May 2025.

Interventions: Patients received nivolumab, 3 mg/kg, and ipilimumab, 1 mg/kg, every 3 weeks for 4 doses, followed by nivolumab, 480 mg, every 4 weeks for 96 weeks, until disease progression or the development of unacceptable toxic effects.

Main outcomes and measures: The co-primary end points were objective response rate (ORR) and 6-month progression-free survival (6-PFS) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, with the secondary end points being median overall survival (mOS), progression-free survival (PFS), and treatment-related toxic effects.

Results: Overall, 52 participants were included. The median (range) age of participants was 62 (29-84) years; 41 (79%) were female individuals and 11 (21%) were male individuals. Overall, 52 patients representing 17 tumor types were enrolled, with the most common tumor type being endometrial cancer (26 [50%]). Twenty-seven patients (52%) were pretreated for metastatic disease. ORR was 63% (95% CI, 50% to 75%) with the median duration of response not being reached and 79% of responses being ongoing. The median PFS and OS have not been reached and the 6-month PFS was 71% (95% CI, 57%-81%). Overall, 12 patients (23%) experienced a grade 3/4 immune-related adverse event.

Conclusions and relevance: This nonrandomized clinical trial found that combined anti-PD-1/CTLA-4 blockade was associated with a high rate of durable responses in dMMR/MSI-H noncolorectal cancers, comparing favorably to published trials using anti-PD-1/programmed cell death ligand 1 monotherapy. Anti-PD-1/CTLA-4 blockade using nivolumab and ipilimumab may represent an alternative treatment option to monotherapy in this patient population.

Trial registration: ClinicalTrials.gov: NCT04969887.