Nivolumab and Ipilimumab Combination Shows Promise for Biliary Tract Cancers

The combination immunotherapy was associated with significant positive outcomes among patients with gallbladder carcinoma and intrahepatic cholangiocarcinoma.

A subgroup analysis of the phase 2 CA209-538 trial published in JAMA Oncology found that the use of combination immunotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy) was associated with significant positive outcomes among patients with gallbladder carcinoma and intrahepatic cholangiocarcinoma.

Researchers suggested that the results observed with this treatment are comparable to those observed with single-agent anti–programmed cell death protein 1 (anti–PD-1) therapy and therefore warrants further investigation.

“This regimen was associated with significantly improved clinical outcomes in patients with gallbladder carcinoma and intrahepatic cholangiocarcinoma, leading to durable responses; this contrasts with the generally short-lived responses obtained with chemotherapy,” the authors wrote.

The prospective, multicenter, nonrandomized trial evaluated patients with advanced rare cancer, including those with biliary tract cancers. The subgroup analysis specifically analyzed 39 patients from CA209-538, the majority of which (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research.

Those included in the subgroup analysis received 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by 3 mg/kg of nivolumab every 2 weeks for up to 96 weeks until disease progression or the development of unacceptable adverse events (AEs). The primary end point of the study was disease control rate as assessed by RECIST 1.1.

Of the total cohort included in the subgroup analysis, the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17). Notably, all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Moreover, responses were only observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma.

“Interestingly, all responding patients in the present study had either gallbladder carcinoma or intrahepatic cholangiocarcinoma, suggesting that response to dual checkpoint inhibitor therapy in [biliary tract cancer] may differ by anatomical site,” the authors wrote. “This may be explained by a different frequency of genomic alterations in genes of the SWI/SNF chromatin remodeling complex between anatomical subtypes that are known to sensitize tumor cells to T-cell mediated killing.”

Importantly though, the median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Overall, immune-related AEs were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events.

“A fifth of patients experienced rapid disease progression after enrollment in the trial and received only 1 or 2 treatment doses, which may reflect the aggressive biology and poor prognosis of patients with advanced [biliary tract cancer] at later stages of their disease and the delayed response kinetics of immunotherapy,” the authors wrote. “However, a negative impact of checkpoint inhibition leading to accelerated tumor growth in this patient population, as has been recognized in other cancers, cannot be excluded.”

Researchers noted that this analysis was conducted in a limited number of patients, and further investigation will be required in a larger cohort of patients.

“The promising activity suggests that this combination may be the preferred immunotherapy regimen for further study in biliary tract cancers,” the authors concluded.


Klein O, Kee D, Nagrial A, et al. Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients with Advanced Biliary Tract Cancers. JAMA Oncology. doi: 10.1001/jamaoncol.2020.2814.

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