In an Australian and New Zealand phase II trial (MOST-CIRCUIT) reported in JAMA Oncology, Carlino et al found that combined anti–PD-1/CTLA-4 blockade was associated with a high rate of durable responses in patients with advanced mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) noncolorectal cancers.
According to the investigators, “MOST-CIRCUIT is the first trial that investigated combined anti–PD-1/CTLA-4 blockade in advanced dMMR/MSI-H noncolorectal cancers.”
Study Details
In cohort D of the multicenter trial, 52 patients enrolled between August 2021 and February 2024 received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for four doses, followed by nivolumab at 480 mg every 4 weeks for 96 weeks or until disease progression or unacceptable toxicity. The co-primary outcome measures were objective response rate and 6-month progression-free survival.
Key Findings
The 52 patients had 17 tumor types, most commonly endometrial cancer (n = 26, 50%); other tumor types observed in more than 1 patient consisted of carcinoma of unknown primary (n = 3) and duodenal cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, ovarian cancer, and urothelial carcinoma (n = 2 each). Overall, 27 patients (52%) had been treated for metastatic disease.
Objective response was observed in 33 patients (63%, 95% confidence interval [CI] = 50%–75%), with complete response in 5 (10%). Among the 26 patients with endometrial cancer, objective response was observed in 58%. Median duration of response was not reached; at the time of analysis, the response range was 2 to ≥ 31 months, with 79% of responses still ongoing.
With a median follow-up of 10.7 months (range = 6.2–38 months), median progression-free survival and median overall survival were not reached. Progression-free survival at 6 months was 71% (95% CI = 57%–81%).
Immune-related adverse events of any grade occurred in 75% of patients; grade 3 or higher events occurred in 12 patients (23%), most commonly hepatitis and enterocolitis. The only non–immune-related adverse events observed were mild infusion reactions and fatigue.
The investigators concluded: “This nonrandomized clinical trial found that combined anti–PD-1/CTLA-4 blockade was associated with a high rate of durable responses in dMMR/MSI-H noncolorectal cancers, comparing favorably to published trials using anti–PD-1/[PD-L1] monotherapy. Anti–PD-1/CTLA-4 blockade using nivolumab and ipilimumab may represent an alternative treatment option to monotherapy in this patient population.”
Oliver Klein, MD, of Olivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, Australia, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the Victorian Government Operational Infrastructure Support Program, a grant from the Minderoo Foundation, and others. For full disclosures of all study authors, visit jamanetwork.com.
