Australian-led trial delivers encouraging results.
A landmark Australian-led phase 2 clinical trial has delivered promising results for patients with advanced gynaecological clear cell cancers (CCCs), a rare and aggressive group of malignancies that historically respond poorly to standard chemotherapy.
The MoST-CIRCUIT study, a prospective multicentre trial conducted across 17 sites in Australia and New Zealand, assessed the efficacy of combined immune checkpoint inhibition using nivolumab (anti–PD–1) and ipilimumab (anti–CTLA-4) in patients with metastatic clear cell ovarian (CCOC) or endometrial (CCEC) cancers.
Of the 28 patients enrolled between August 2021 and February 2024, most (86%) had CCOC, and nearly 70% had previously received one line of systemic therapy. Patients were treated with four induction cycles of nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) every three weeks, followed by maintenance nivolumab (480 mg every four weeks) for up to 96 weeks or until disease progression or unacceptable toxicity.
High response rate and durable outcomes
The objective response rate (ORR) across the cohort was 54% (95% CI, 35–71), with three complete responses (12%) and twelve partial responses (42%). Response rates were consistent between tumour types—55% in CCOC and 50% in CCEC.
Notably, all responses were ongoing at the time of reporting, and the median duration of response and overall survival had not yet been reached. The six-month progression-free survival (PFS) was 58% (95% CI, 39–74), further supporting the potential durability of immunotherapy in this setting.
Safety profile
While the combination regimen was generally tolerable, immune-related adverse events (irAEs) were common. Grade 3 or 4 irAEs occurred in 35% of patients, with one treatment-related death from myocarditis. These results underscore the importance of close monitoring and multidisciplinary management in patients receiving dual checkpoint blockade.
Clinical Implications
Gynaecological CCCs are often characterised by resistance to platinum-based chemotherapy and carry a poor prognosis when diagnosed at an advanced stage. Currently, there are no standard treatments beyond first-line therapy. These findings position combined PD-1/CTLA-4 inhibition as a promising therapeutic avenue in this high-need population.
“In this nonrandomised clinical trial, immunotherapy using combined anti–PD-1/CTLA-4 blockade demonstrated encouraging activity with a high rate of durable responses in patients with advanced gynaecological CCCs. This regimen should be further investigated in this patient population with unmet medical need,” the investigators concluded.
With few effective options available for this patient group, the results from MoST-CIRCUIT mark a significant step forward in personalising immunotherapy for rare gynecological cancers.
Paper: Gao, B., et al. Nivolumab and Ipilimumab Combination Treatment in Advanced Ovarian and Endometrial Clear Cell Cancers: A Nonrandomized Clinical Trial. JAMA Oncol. doi:10.1001/jamaoncol.2025.1916. Published online July 3, 2025. Access online here.
