Nivolumab + Ipilimumab in dMMR/MSI-H Noncolorectal Cancers: Outperforming Single-Agent Therapy
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On November 13, 2025, JAMA Oncology published a study showing how dual immunotherapy (nivolumab + ipilimumab) can produce strong, durable responses in highly immunogenic tumors known as dMMR/MSI-H. Until now, PD-1 monotherapy has mostly been used for dMMR/MSI-H tumors outside the colon. This study showed for the first time that combining anti–PD-1 and anti–CTLA-4 blockade substantially increased the objective response rate (from around 35% to 63%) and that most responses continued for months. These findings suggest that treatment approaches may be reshaped for this rare and biologically complex tumor group.
Why Was a Combination Needed?
DNA mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) causes a high tumor mutational burden and, consequently, many neoantigens. This makes the tumor “visible” to the immune system. In 2017, the FDA ushered in a new era in oncology by approving anti-PD-1 agents such as pembrolizumab and nivolumab for this group, regardless of tumor location.
However, clinical practice did not always deliver the miraculous responses expected. While single-agent PD-1 produced response rates of 40-50% in colorectal cancer (CRC), the rate in noncolorectal dMMR tumors remained at 30-35%. More than half of patients showed primary resistance or early progression.
The Study’s Scientific Hypothesis
We know from melanoma and renal cell carcinoma trials that CTLA-4 blockade (ipilimumab)increases early T-cell activation (in lymph nodes), while PD-1 blockade (nivolumab) prevents exhaustion in the tumor microenvironment. MOST-CIRCUIT was designed to test whether this synergy could also overcome resistance in noncolorectal MSI-H tumors.
Study Design and Methodology
This multicenter, single-arm, Phase II trial, conducted at centers in Australia and New Zealand, included advanced cancer patients resistant to standard treatments or without alternatives.
- Total Patients: 52
- Key Criterion: Histologically confirmed advanced dMMR/MSI-H noncolorectal solid tumors.
- Predominant Tumor: 50% of patients had endometrial (uterine) cancer. Others included gastric, small bowel, pancreatic and ovarian cancers.
Every 3 weeks, for a total of 4 doses.
Every 4 weeks.
*Note: Choosing an Ipilimumab dose of 1 mg/kg is a strategic decision to reduce toxicity (3 mg/kg is used in melanoma).
Results: Efficacy Beyond Expectations
The primary endpoints were Objective Response Rate (ORR) and 6-month Progression-Free Survival (PFS). The data revealed a statistically significant and clinically impressive difference compared with historical single-agent data.
An Important Note: At the end of the median follow-up period, median overall survival (OS) and median progression-free survival (PFS) had not yet been reached. This suggests that efficacy in responding patients was long-lasting (durable) . High response rates similar to those in the overall population were also observed in the endometrial cancer subgroup.
Safety Profile: How Heavy Is the Cost?
The greatest concern with dual immunotherapy is increased toxicity. In particular, high-dose ipilimumab (3 mg/kg) is known to cause serious autoimmune side effects. However, the trial’s low-dose ipilimumab (1 mg/kg) regimen successfully kept toxicity within manageable limits.
- The most common serious side effects were abnormal laboratory findings (elevated AST/ALT - hepatitis) and diarrhea/colitis.
- No treatment-related deaths (Grade 5 toxicity) occurred.
- 14% of patients had to stop treatment because of side effects (Discontinuation rate). This is similar to colorectal cancer data from CheckMate-142 (13%).
What Will the Implications for Clinical Practice Be?
MOST-CIRCUIT demonstrates that dMMR/MSI-H tumor biology is not limited to colorectal cancer and that, in noncolorectal tumors too, combined immunotherapy (Nivo+Ipi) may be a powerful treatment option.
Although this was not a randomized Phase 3 trial, a response rate as high as 63% and lasting disease control could bring this combination to the forefront, particularly for patients who do not respond to single-agent therapy or have a high tumor burden. The study once again confirmed the power of a “tumor-agnostic” treatment approach, independent of where the cancer originated.
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