Highlight
This nonrandomized multicenter phase 2 trial demonstrates that the combination of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) yields a high objective response rate (54%) and durable responses in advanced gynecological clear cell cancers (CCCs), which traditionally have poor chemotherapy response rates. Notably, the 6-month progression-free survival was 58%, and median overall survival has not been reached, despite 35% of patients experiencing grade 3-4 immune-related adverse events. These findings suggest a substantial clinical benefit and warrant further investigation of this immunotherapy regimen in this underserved patient population.
Study Background and Disease Burden
Gynecological clear cell cancers, including clear cell ovarian cancer (CCOC) and clear cell endometrial cancer (CCEC), represent aggressive malignant neoplasms characterized by resistance to standard chemotherapy and high mortality rates, especially when metastatic. These malignancies account for a minority of gynecologic cancer cases but disproportionately contribute to poor clinical outcomes due to their chemo-refractory nature and propensity for early dissemination. Despite advances in cancer therapeutics, effective systemic treatments for advanced gynecological CCCs remain limited, constituting a pressing unmet medical need. Immune checkpoint inhibitors targeting PD-1 and CTLA-4 pathways have revolutionized treatment in several malignancies. However, data on their efficacy in gynecological CCCs are sparse. Thus, evaluating combined checkpoint blockade in this subset offers new therapeutic hope.
Study Design
The MoST-CIRCUIT clinical trial is a prospective, multicenter, single-arm phase 2 study assessing the efficacy of combined anti-PD-1 and anti-CTLA-4 immunotherapy in patients with advanced rare cancers, including gynecological CCCs. From August 2021 to February 2024, 28 patients with advanced CCOC (24 patients) or CCEC (4 patients) who had received no more than one prior systemic therapy were enrolled at 17 sites across Australia and New Zealand. The intervention comprised nivolumab administered intravenously at 3 mg/kg combined with ipilimumab at 1 mg/kg every 3 weeks for four doses, followed by maintenance nivolumab 480 mg every 4 weeks for up to 96 weeks or until disease progression or unacceptable toxicity. The coprimary endpoints were objective response rate (ORR) and 6-month progression-free survival (PFS), both assessed by RECIST 1.1 criteria. Secondary endpoints included median overall survival (OS), PFS duration, and safety/tolerability profile.
Key Findings
Among the 28 treated patients (median age 55 years, range 34-77), 68% had prior systemic therapy. The overall ORR was 54% (95% confidence interval [CI], 35%-71%), with 3 patients (12%) achieving complete responses and 12 (42%) partial responses. Stratified by cancer subtype, the ORR was 55% (95% CI, 35%-73%) for CCOC and 50% (95% CI, 9%-91%) for CCEC. Importantly, the median duration of response had not yet been reached at data cutoff, with all responses ongoing, indicating durable antitumor activity. The 6-month PFS rate was 58% (95% CI, 39%-74%), and median OS was not reached. These outcomes compare favorably with historical data demonstrating limited efficacy with chemotherapy in this population.
Regarding safety, 9 patients (35%) experienced grade 3 or 4 immune-related adverse events (irAEs), consistent with the known toxicity profile of dual checkpoint inhibition. One treatment-related death occurred due to grade 5 myocarditis—an uncommon but severe irAE. Other toxicities were manageable with established immunosuppressive protocols. The risk-benefit balance remains favorable given the lack of alternative effective options.
Expert Commentary
The MoST-CIRCUIT study findings mark a significant advance by demonstrating encouraging clinical activity of combined nivolumab and ipilimumab in a rare and chemotherapy-resistant subgroup of gynecological cancers. The high ORR and durable responses highlight the potential of dual immune checkpoint blockade to overcome immune evasion mechanisms inherent to clear cell histologies. This aligns with growing evidence supporting immunotherapy’s role beyond traditionally immunogenic tumors.
However, interpretation should consider the single-arm, nonrandomized study design and limited sample size, especially for endometrial clear cell cancer, which constrains definitive efficacy conclusions and generalizability. Future randomized controlled trials are warranted to compare this regimen against standard therapies and to identify predictive biomarkers that could refine patient selection. Additionally, mechanistic studies investigating the tumor microenvironment and immune infiltrate characteristics could elucidate response determinants and resistance pathways.
Clinicians should also be vigilant for immune-related toxicities, particularly myocarditis, which, although rare, may be fatal. Early detection and prompt management protocols are critical to optimizing outcomes.
Conclusion
The combination of nivolumab and ipilimumab represents a promising therapeutic approach in advanced gynecological clear cell carcinomas, with a remarkable ORR of over 50% and durable responses in a patient population with previously limited options. Despite notable immune-related toxicities, the treatment offers meaningful clinical benefit, underscoring the importance of further investigation in larger, controlled trials to confirm efficacy and safety profiles. Addressing this unmet need could substantially improve prognosis and quality of life for patients afflicted by these aggressive malignancies.
References
- Gao B, Carlino MS, Michael M, et al. Nivolumab and Ipilimumab Combination Treatment in Advanced Ovarian and Endometrial Clear Cell Cancers: A Nonrandomized Clinical Trial. JAMA Oncol. 2025 Jul 3:e251916. doi:10.1001/jamaoncol.2025.1916.
- Mirza MR, Duran I, Goodman A. Immunotherapy in Gynecologic Oncology: Current and Future Perspectives. J Clin Oncol. 2022;40(14):1565-1574.
- Meyer LA, Broaddus RR, Lu KH. Gynecologic Malignancies: Treatment Advances and Future Directions. Hematol Oncol Clin North Am. 2023;37(1):43-59.
- Hodi FS, O’Day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med. 2010;363(8):711-723.
