A phase II clinical trial has demonstrated promising efficacy for nivolumab monotherapy in patients with advanced refractory biliary tract cancer, achieving a 22% objective response rate and durable responses lasting up to two years. The study, which enrolled 54 patients with biliary tract cancers who had progressed on at least one prior systemic therapy, represents a significant development for a patient population with limited treatment options.
Study Design and Patient Population
The single-arm phase II study utilized a Simon two-stage design to evaluate nivolumab 240mg intravenously every two weeks for 16 weeks, followed by 480mg every four weeks until disease progression or unacceptable toxicity. Patients had histologically proven biliary tract cancer and had failed one to three lines of prior systemic therapy.
The enrolled population included 50% female patients with a median age of 65 years. Primary tumor sites comprised intrahepatic cholangiocarcinoma (63%), gallbladder cancer (26%), and extrahepatic cholangiocarcinoma (11%). Notably, 56% of patients had failed only one line of therapy, while 44% had failed multiple lines.
Efficacy Results
Among 45 evaluable patients, 10 achieved partial responses (22%), including one unconfirmed partial response, while 17 patients (37.8%) achieved stable disease, resulting in a disease control rate of 60%. All responding patients were microsatellite stable. With a median follow-up of 13.34 months, the median progression-free survival reached 3.98 months (95% CI: 2.33-5.98), and median overall survival was 14.22 months (95% CI: 6.64-NA).
The survival data showed 6-month and 12-month overall survival rates of 71.4% and 52.3%, respectively, while 6-month and 12-month progression-free survival rates were 35.2% and 24.1%.
Safety Profile
Nivolumab demonstrated a favorable safety profile in this heavily pretreated population. The most common treatment-related adverse event was increased alkaline phosphatase, occurring in 24.5% of patients. Grade III/IV treatment-related adverse events occurred in 11 patients (20.4%), with hyponatremia being most frequent (3 patients) followed by elevated alkaline phosphatase (2 patients). Importantly, no treatment-related adverse events led to study drug discontinuation.
Combination Approach with Radiation Therapy
A separate randomized phase 2 study evaluated the combination of stereotactic body radiotherapy (SBRT) with nivolumab alone or with ipilimumab in 61 patients with refractory biliary tract cancer. The study used a 1:1 randomization stratified by performance status, with SBRT delivering 15 Gy combined with immunotherapy.
The SBRT/nivolumab arm showed limited activity with no responses observed and a clinical benefit rate of only 11% (95% CI 1-33), leading to early closure after the first stage. However, the SBRT/nivolumab/ipilimumab combination demonstrated improved activity with a clinical benefit rate of 31% (95% CI 18-47) and an overall response rate of 11.9% (95% CI 4.0-25.6).
Among five patients achieving partial responses in the combination arm, the median duration of response was 4.4 months (95% CI 0.0-9.2). Both treatment arms showed similar progression-free survival of 1.7 months and overall survival of approximately 5 months.
Safety of Combination Therapy
The addition of ipilimumab increased toxicity, with grade 3 or higher treatment-related adverse events occurring in 16% of patients receiving SBRT/nivolumab versus 31% in the combination arm. One patient death due to hepatitis occurred in the combination arm, highlighting the need for careful patient selection and monitoring.
Clinical Implications
These results represent meaningful progress for biliary tract cancer patients, who face limited therapeutic options after first-line treatment failure. The 22% response rate with nivolumab monotherapy, combined with durable responses and manageable toxicity, supports the rationale for PD-1 inhibition in this indication. The investigators noted that tissue samples were collected from all patients for correlative studies, including PD-L1 status evaluation, which may help identify biomarkers for patient selection.
The findings warrant further investigation through randomized controlled trials to establish the role of immunotherapy in refractory biliary tract cancer treatment algorithms.
