Efficacy Analysis of Nivolumab in Combination with Gemcitabine and Cisplatin in Patients with Unresectable or Metastatic Biliary Tract Cancers

Background: Current chemotherapy for advanced biliary tract cancers has limited efficacy. This study aimed to determine the efficacy and safety of nivolumab in combination with gemcitabine and cisplatin and biomarkers for predicting response and prognosis. Methods: In this open-label, single-arm, phase Ⅱ trial, enrolled patients received gemcitabine 1000mg/m2 on day 1 and d 5, followed by cisplatin 75mg/m2 on day 1 and nivolumab 3mg/kg on day 3 in every 3-week treatment cycle. Responsive patients switched to maintenance therapy after a maximum of six cycles combination therapy. The primary outcome was objective response. Secondary outcomes included safety, disease control, progression free survival and overall survival. Findings: Between November 16, 2017, and December 31, 2018, 27 of 32 enrolled patients received a median of 4 cycles (IQR, 3-6) combination therapy with a median follow-up of 12.8 (95% CI, 10.8-14.8) months. 15 (55.6%) patients achieved objective response and the disease control was 92.6%. 2 of 6 (33.3%) response evaluable patients previously treated with gemcitabine- or cisplatin-based chemotherapy achieved 1 complete response and 1 partial response.13 of 21 chemotherapy-naive patients (61.9%) achieved objective response. Median progression free survival was 6.1 months (95% CI, 3.4 -8.2), and progression free survival at 6-month was 51.9 % (95% CI, 31.9-68.6). Median overall survival was 12.5 months (95% CI, 5.0-NR), and overall survival at 12-month was 54% (95% CI, 33.1- 70.9). The most common grade 3 or higher adverse events were thrombocytopenia (56%), and neutropenia (22%). PD-L1 was invalid for predicting response and prognosis. MSI and Fitness could predict response. TNB, sFASL and IFN-γ in serum may predict prognosis. Interpretation: Nivolumab in combination with gemcitabine and cisplatin had promising efficacy and manageable safety profile in unresectable or metastatic biliary tract cancers. Clinical Trial Registration: (NCT03311789). Funding Statement: This research was supported by the grants from the Natural Science Foundation of China (No. 81830002 and 31870873 to WDH, No. 81773248, 81572914 to Qian Mei), the National Key Research and Development Program of China (No. 2016YFC1303501 and 2016YFC1303504 to WDH). Declaration of Interests: There was no commercial funding in this study. All authors declared no competing interests. Ethics Approval Statement: The study protocol was approved by the institutional ethics committee and conducted in accordance with international standards of good clinical practice. Written informed consent based on Declaration of Helsinki principles was provided by patients or their representatives before study entry.