Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study
The prognosis of patients with unresectable or metastatic biliary tract cancer (BTC) is unacceptable low. This study aimed to determine the efficacy, safety and predicting biomarkers of immune checkpoint inhibitor nivolumab in combination with chemotherapy in advanced BTCs. Methods: In this open-label, single-arm, phase Ⅱ trial, chemo-immunology combination therapy consisting of gemcitabine 1000mg/m 2 , cisplatin 75mg/m 2 plus nivolumab 3mg/kg was administered every 3 weeks for up to 6 cycles.
... or up to 6 cycles. Maintenance treatment with gemcitabine plus nivolumab was administered to patients achieving disease control following the combination therapy. The primary outcome was objective response rate (ORR). Secondary outcomes included safety, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). The exploratory objectives were to assess biomarkers for predicting clinical response and prognosis. Results: 32 patients with a median age of 60 (range 27-69) years were enrolled. As of September 31, 2019, the median follow-up was 12.8 (95% CI, 10.8-14.8) months. 27 response-evaluable patients received a median of 4 (IQR, 3-6) cycles combination therapy, of which 15 (55.6%) patients achieved objective response, including 5 (18.6%)with complete response (CR), and the DCR was 92.6%. 2 of 6 patients in cohort A who were refractory to gemcitabine or cisplatin-based chemotherapy achieved 1 CR and 1 partial response. 13 of 21 chemotherapy-naive patients (61.9%) in cohort B achieved objective response. The median PFS of all patients in cohort A+B was 6.1 months. The median OS was 8.5 months with 33.3% 12-month OS rate. The most frequent grade 3 or higher adverse events were thrombocytopenia (56%), and neutropenia (22%). Fitness might be a biomarker for predicting clinical response. On-therapy change of serum sFASL, MCP-1 and IFN-γ were correlated with prognosis. Conclusions : Nivolumab in combination with gemcitabine and cisplatin offer promising efficacy and manageable safety profile for patients with advanced BTCs. Background Biliary tract cancers (BTCs) represent a diverse group of highly invasive heterogeneous epithelial cancers arising from the biliary tract with poor prognosis. Base on their anatomic location, BTCs are classified into gallbladder carcinoma (GBCA), intrahepatic cholangiocarcinoma (iCCA), perihilar 4 cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). The incidence of BTCs increased globally over the past few decades , with reported prevalence of 235,900 patients diagnosed with BTCs in 2017 . Surgical resection is a curative treatment option for early-stage BTCs, however, most patients with BTCs already have locally advanced or metastatic disease at the time of diagnosis. Even in cases of surgical resection, recurrence is seen in > 60% of patients within the first or the second year . For patients with advanced unresectable or metastatic BTCs, gemcitabine plus cisplatin is the current standard first-line systemic therapy . However, this combination regimen confers a limited efficacy, one possible reason is the rich desmoplastic stroma of BTCs, forming a barrier to the delivery of chemotherapeutic drugs in the tumor bed, and resulting in resistance to chemotherapy. Other regimens or strategies, such as gemcitabine and oxaliplatin with or without cetuximab , capecitabine plus cisplatin , nab-paclitaxel and gemcitabine , and small molecule kinase inhibitors targeting FGFR, IDH, MET, Mesothelin, BRCA and other mutated genes, did not show significant improvements of efficacy and survival [8, 9] .