Nivolumab in Combination with Gemcitabine and Cisplatin for Advanced Unresectable or Metastatic Biliary Tract Cancers: Results from a Single Center, Single-Arm, Phase I Study

Abstract

Background: Current first-line chemotherapy for advanced unresectable or metastatic biliary tract cancers has limited efficacy. We assessed the safety and activity of anti-programmed death 1 (anti-PD-1) antibody nivolumab in combination with gemcitabine plus cisplatin in patients with advanced unresectable or metastatic biliary tract cancers. Methods: This study was a single-center, single-arm, open-label, phase I trial. Eligible patients received a maximum of six cycles combination therapy of gemcitabine (1000mg/m2) and cisplatin (75mg/m2) plus nivolumab (3mg/kg) every 3 weeks. Responsive patients switched to maintenance therapy with nivolumab plus gemcitabine or nivolumab alone. The primary objective was to assess the safety and progression free survival at 6 months. Between May 16, 2017, and July 31, 2018, 32 eligible patients were enrolled, and 27 response-evaluable patients received a median of 4 cycles (IQR, 3-6) combination therapy. The most common grade 3 or higher adverse events were thrombocytopenia (56%), and neutropenia (22%). 15 (55.6%) patients achieved objective response, including 5 (18.6%) complete response and 10 (37%) partial response, the disease control rate was 92.6%. At data cutoff, median progression free survival was 6.1 months (95% CI, 3.4 -8.2), and progression free survival at 6 months was 51.9 % (95% CI, 31.9-68.6). Median overall survival was 12.5 months (95% CI, 5.0-NR), the 12-month overall survival rate were 54% (95% CI, 33.1- 70.9). Treatment cycles (≥4) could predict better progression free survival and overall survival (HR 0.595, [95% CI, 0.398-0.89], p=0.012). Baseline percentage of CD3+ cells, increase of IFNγ+CD8+ cells, and decrease of IL-2, IL-18, soluble FasL and CCL2 in peripheral blood were biomarkers in predicting response. Interpretation: Nivolumab in combination with gemcitabine and cisplatin had a manageable safety profile and promising antitumor efficacy in advanced unresectable or metastatic biliary tract cancers. 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.