{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:31:40Z","timestamp":1793320300660,"version":"4.5.0"},"reference-count":34,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"Importance<\/jats:title>Gynecological clear cell cancers (CCCs) are aggressive malignant neoplasms with low response rate to chemotherapy. The treatment of patients with metastatic disease remains an area of significant unmet need.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate the efficacy of combined anti\u2013programmed cell death 1 protein (PD-1)\/cytotoxic T-lymphocyte\u2013associated protein 4 (CTLA-4) blockade using nivolumab and ipilimumab in advanced gynecological CCCs.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>The MoST-CIRCUIT prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced selected rare cancers. Patients with advanced clear cell ovarian cancer (CCOC)\/clear cell endometrial cancer (CCEC) with a maximum of 1 course of prior systemic therapy were enrolled from August 2021 to February 2024 across 17 Australian and New Zealand sites.<\/jats:p><\/jats:sec>Interventions<\/jats:title>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.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>Coprimary end points were objective response rate (ORR) and 6-month progression-free survival (PFS) as assessed by RECIST version 1.1 criteria, with the secondary end points being median overall survival, PFS, and treatment-related toxic effects.<\/jats:p><\/jats:sec>Results<\/jats:title>Of 28 included patients, the median (range) age was 55 (34-77) years. A total of 24 had CCOC and 4 had CCEC; 19 (68%) had a previous course of therapy. Overall ORR was 54% (95% CI, 35-71), with 3 (12%) with complete response and 12 (42%) with partial response; the ORR was 55% (95% CI, 35-73) in the CCOC group and 50% (95% CI, 9-91) in the CCEC group. The median duration of response has not been reached, with all responses ongoing. The 6-month PFS was 58% (95% CI, 39-74), and the median overall survival has not been reached. A total of 9 patients (35%) experienced a grade 3 or 4 immune-related adverse event, and a grade 5 myocarditis occurred in 1 patient.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this nonrandomized clinical trial, immunotherapy using combined anti\u2013PD-1\/CTLA-4 blockade demonstrated encouraging activity with a high rate of durable responses in patients with advanced gynecological CCCs. 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