Nivolumab for Advanced Refractory Biliary Tract Cancer

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In a phase II trial reported in JAMA Oncology, Kim et al found that nivolumab showed antitumor activity in patients with advanced refractory biliary tract cancer.

As noted by the investigators, there currently is no established second-line systemic treatment for biliary tract cancer.

Study Details

The multicenter investigator-initiated study enrolled 54 patients between October 2016 and December 2018, with all patients receiving study treatment. Of these, 46 were examined for objective response with radiologic imaging. Patients had to have progressive disease after at least one and no more than three prior lines of systemic therapy. Nivolumab was given at 240 mg every 2 weeks for 16 weeks followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate on RECIST version 1.1 criteria.


Investigator-assessed objective responses (all partial responses) were observed in 10 (22%) of 46 patients. An additional 17 patients (37%) had stable disease, yielding a disease control rate of 59%. On central independent review, responses (all partial) were observed in 5 patients (11%); stable disease was observed in 18 (39%), yielding a disease control rate of 50%. All responses were observed in patients with mismatch repair protein–proficient tumors. With median follow-up of 12.4 months, median duration of investigator-assessed response was not reached; four responders had response lasting ≥ 12 months at time of analysis. Data on programmed cell death ligand 1 (PD-L1) expression status were available for 42 patients, with 18 having PD-L1–positive tumors (≥ 1% of tumor cells). Nine of the 10 investigator-assessed responders had PD-L1–positive tumors.


  • Objective response was observed in 22% of patients, and the disease control rate was 59%.
  • Most responders had PD-L1–positive tumors and progression-free survival was longer among patients with PD-L1–positive tumors.

Among all 54 patients, median progression-free survival was 3.68 months and median overall survival was 14.24 months. Patients with PD-L1–positive tumors had significantly prolonged progression-free survival (median = 10.4 vs 2.3 months, hazard ratio [HR] = 0.23, P < .001) and nonsignificantly prolonged overall survival (median = not reached vs 10.8 months, P = .19) vs patients with PD-L1–negative tumors.

Adverse Events

Grade 3 or 4 treatment-related adverse events occurred in 9 (17%) of 54 patients, with the most common being hyponatremia (6%) and increased alkaline phosphatase (4%). Immune-mediated adverse events of any grade occurred in 52% of patients, with the most common being increased aspartate aminotransferase (20%), increased alanine aminotransferase (17%), diarrhea (11%), rash (9%), infusion-related reactions (7%), and pruritus (7%). Grade 3 immune-mediated events occurred in two patients (colitis and adrenal insufficiency).

The investigators concluded, “This study found that nivolumab was well tolerated and showed modest efficacy with durable response in patients with refractory biliary tract cancer. Further studies are warranted to verify the findings and evaluate biomarkers for improved treatment selection for patients.”

Richard D. Kim, MD, of the Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Bristol-Myers Squibb. For full disclosures of the study authors, visit