Nivolumab and Ipilimumab in Rare, Aggressive Gynecologic Tumors

Clear-cell carcinomas of the ovary and endometrium are rare, treatment-resistant gynecologic cancer subtypes. They respond poorly to conventional chemotherapy and have an unfavorable course even from early stages. An effective, durable strategy is currently lacking.

Based on preliminary evidence that checkpoint inhibitors may be effective in this histological subtype, the MoST-CIRCUIT phase 2 study in Australia and New Zealand tested combination immunotherapy. The findings are striking.

📚Results were published on July 3, 2025, in one of the world's most respected oncology journals, JAMA Oncology.

MoST-CIRCUIT Summary and Patient Characteristics

• Design: Phase 2, multicenter, open-label, nonrandomized
• Participants: 28 patients (24 ovarian clear-cell carcinoma, 4 endometrial clear-cell carcinoma)
• Median age: 55 (range: 34–77)
• Prior chemotherapy: 68% (19 patients)
• Treatment protocol:
  • Induction: Nivolumab (3 mg/kg) + ipilimumab (1 mg/kg), 1 time every 3 weeks for 4 cycles
  • Continuation: Nivolumab (480 mg) every 4 weeks, up to 2 years

Efficacy: Survival and Response Rates

🔹 Objective Response Rate (ORR)

• Overall: 54% (14/26 patients)
  • Complete response (CR): 12% (3 patients)
  • Partial response (PR): 42% (11 patients)
• Ovarian subgroup (CCOC): 55%
• Endometrial subgroup (CCEC): 50%

🔹 Progression-Free Survival (PFS)

• 6-month PFS: 58%
• Median PFS: 10 months
• Median overall survival: Not yet reached
• All responses remained ongoing at data cut-off (9–33 months)

A Comparative View: What Does This Success Mean?

The 54% response rate was substantially higher than in earlier comparable studies:

• BrUOG 354: Combination immunotherapy ORR 33%, nivolumab alone 14%
• DART S1609: ORR 21.1%

Earlier treatment and maintenance nivolumab may partly explain the difference.

Safety Profile and Side Effects

• Any-grade immune-related adverse effects: 78% (22 patients)
• Severe (≥ grade 3) adverse effects: 35% (10 patients)
  • Most common: Hepatitis
• Fatal adverse effect: 1 patient died from immune-mediated myocarditis

The authors emphasize that close monitoring and rapid intervention are vital.

Genetic Findings: Who Benefits More?

Tumor Mutational Burden (TMB)

• Median TMB: 3.1 mut/Mb (generally low)
• Responders had significantly higher TMB than nonresponders (4.7 vs 1.8 mut/Mb)

Genetic Mutations

• Most common mutations:
  • ARID1A (50%)
  • PIK3CA (45%)
  • SPOP, ZNF217 (27–23%)

Although ARID1A mutation was previously associated with greater immunotherapy sensitivity, this study found no significant relationship between ARID1A status and response.

Interestingly, all 4 patients with TERT promoter mutations responded. This may be a promising biomarker requiring validation in larger studies.

Conclusion and Future Perspective

This phase 2 study suggests nivolumab + ipilimumab can be effective and provide durable benefit in some advanced clear-cell gynecologic cancers. Larger randomized phase 3 trials are needed before direct clinical adoption.

What is already clear:

📌 Combination immunotherapy is a promising option in these rare, aggressive cancer subtypes.