Nivolumab Plus Ipilimumab Shows Encouraging Activity in Advanced Gallbladder Carcinoma Despite Limited Overall Efficacy in Biliary Tract Cancer
Results from the Phase 2 MoST-CIRCUIT Trial
Results from the Phase 2 MoST-CIRCUIT Trial
Clinical Summary:
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Design/Population: The phase 2 MoST-CIRCUIT trial evaluated nivolumab plus ipilimumab in patients with advanced intrahepatic cholangiocarcinoma or gallbladder carcinoma who had received no more than one prior line of systemic therapy.
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Key Outcomes: Overall clinical activity was modest, but patients with gallbladder carcinoma achieved substantially higher response rates than those with intrahepatic cholangiocarcinoma, particularly among immunotherapy-naïve patients. The combination demonstrated a manageable safety profile.
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Clinical Relevance: These findings suggest dual PD-1/CTLA-4 blockade may provide greater clinical benefit in gallbladder carcinoma than in other biliary tract cancers and warrant further evaluation in this patient population.
Results from the phase 2 MoST-CIRCUIT trial demonstrated that nivolumab plus ipilimumab produced modest overall activity in advanced biliary tract cancers but demonstrated encouraging efficacy in patients with gallbladder carcinoma, supporting further evaluation of dual immune checkpoint blockade in this subgroup.
“Anti–PD-1/PD-L1 blockade combined with chemotherapy has become the first-line treatment for advanced biliary tract cancers,” stated Adnan Nagrial, MD, PhD, Blacktown and Westmead Hospitals, Sydney, Australia, and coauthors. “Combined anti–PD-1/CTLA-4 blockade using nivolumab and ipilimumab has shown encouraging activity in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma.”
In cohort B of this single-arm, non-randomized trial, investigators enrolled 60 patients with advanced intrahepatic cholangiocarcinoma (n = 37) or gallbladder carcinoma (n = 23). Most patients (n = 51) had received no more than one prior line of systemic therapy, including patients who previously received durvalumab (n = 13). Patients received 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses followed by 480 mg of nivolumab every 4 weeks for up to 96 weeks. The primary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points included overall survival (OS) and safety.
Overall clinical activity was modest. The ORR was 12%, including complete responses in 2% of patients and partial responses in 10% of patients. The 6-month PFS rate was 27%, and median OS was 7 months.
Clinical activity was substantially greater among patients with gallbladder carcinoma than among those with intrahepatic cholangiocarcinoma. ORRs were 26% and 3%, respectively, while 6-month PFS rates were 39% and 19%. Among patients who had not previously received immunotherapy, the ORR increased to 19% overall, including 38% in patients with gallbladder carcinoma compared with 10% in those with intrahepatic cholangiocarcinoma.
The combination demonstrated a manageable safety profile. Grade ≥3 immune-related adverse events occurred in 20% of patients.
“Efficacy was limited in what is the largest biliary tract cancer cohort treated to date with combined anti–CTLA-4/PD-1 blockade… [However] encouraging activity was observed in the [gallbladder cancer] subgroup,” concluded Dr Nagrial et al. “Further evaluation of checkpoint inhibition in biliary tract cancer should focus on patients with [gallbladder cancer].”
Source:
Nagrial A, Carlino MS, Gunjur A, et al. Nivolumab and ipilimumab combination treatment in patients with advanced intrahepatic cholangiocarcinoma and gallbladder cancer: Results from the phase II MoST-CIRCUIT trial. Clin Cancer Res. Published online: June 4, 2026. doi: 10.1158/1078-0432.CCR-25-4009
