Nivolumab and Ipilimumab in Advanced Mismatch Repair-Deficient/Microsatellite Instability-High Noncolorectal Cancers: A Nonrandomized Clinical Trial
- Author(s)
- 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;
- Journal Title
- JAMA Oncology
- Publication Type
- Online publication before print
- 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 OUTCOME 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 registration: NCT04969887.
- Department(s)
- Medical Oncology
- Publisher's Version
- https://doi.org/10.1001/jamaoncol.2025.4721
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-12-04 05:58:00
Last Modified: 2025-12-04 05:59:00