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

Abstract

BackgroundThe prognosis of patients with unresectable or metastatic biliary tract cancer (BTC) is unacceptably low. This study aimed to determine the efficacy, safety and predictive biomarkers of the immune checkpoint inhibitor nivolumab in combination with chemotherapy in advanced BTCs.MethodsIn this open-label, single-arm, phase II trial, a chemotherapy and immunotherapy combination consisting of gemcitabine 1000 mg/m2, cisplatin 75 mg/m2and nivolumab 3 mg/kg was administered every 3 weeks for up to six cycles. Maintenance treatment with gemcitabine plus nivolumab was administered to patients achieving disease control following the combination therapy. The primary outcome was the objective response rate. Secondary outcomes included safety, disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). The exploratory objective was to assess biomarkers for predicting clinical response and prognosis.ResultsThirty-two 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 to 14.8) months. Twenty-seven response-evaluable patients received a median of 4 (IQR, 3–6) cycles of combination therapy, of whom 15 (55.6%) patients achieved an objective response, including 5 (18.6%) with a complete response (CR), and the DCR was 92.6%. Of the six patients in cohort A who were resistant to gemcitabine-based or cisplatin-based chemotherapy, one achieved CR and one achieved partial response. Thirteen of 21 chemotherapy-naive patients (61.9%) in cohort B achieved an objective response. The median PFS of all patients in cohorts A+B was 6.1 months. The median OS was 8.5 months, with a 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 changes in serum soluble FasL, MCP-1 and interferon-γ were correlated with prognosis.ConclusionsNivolumab in combination with gemcitabine and cisplatin offers promising efficacy and a manageable safety profile for patients with advanced BTCs.Trial registration numberNCT03311789

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

“…15 Recently, the whole-exome sequencing in one phase II study shown that TMB, tumor neoantigen burden (TNB), and the mutation of RYR2, MUC4, and APOB could predict the efficacy of nivolumab plus gemcitabine and cisplatin for BTCs. 16 However, no other extensive analyses of genomic correlates of immunotherapy response have been carried out in BTCs.…”

Latest evidence on immunotherapy for cholangiocarcinoma (Review)

“…No significant survival benefit was observed for this combination when compared with other combinations in clinical trials ( 56 – 58 ). However, it has promising efficacy and a manageable safety profile in patients with advanced CCA ( 56 ). Patients with iCCA with high insertion-deletion ratios can also benefit from treatment with this combination ( 59 ).…”

“…Of the 6 patients who were resistant to gemcitabine-based or cisplatin-based chemotherapy, one CR and one PR were achieved. This result indicates that, as a PD-1 inhibitor, nivolumab is able to resensitize BTC to gemcitabine and cisplatin chemotherapy ( 56 ). No significant survival benefit was observed for this combination when compared with other combinations in clinical trials ( 56 – 58 ).…”

“…This result indicates that, as a PD-1 inhibitor, nivolumab is able to resensitize BTC to gemcitabine and cisplatin chemotherapy ( 56 ). No significant survival benefit was observed for this combination when compared with other combinations in clinical trials ( 56 – 58 ). However, it has promising efficacy and a manageable safety profile in patients with advanced CCA ( 56 ).…”

“…The aforementioned results may be due to the synergistic effect of chemotherapy and ICIs; it is suggested that the use of an ICI increased the efficacy of gemcitabine, which in turn increased the antigenicity of tumor cells and partially reduced the immunosuppressive effect of chemotherapy, which may be associated with the role of tumor-associated macrophages ( 56 ). Therefore, the addition of a PD-1 inhibitor to a chemotherapy regimen can better control the disease, benefit the patients and attenuate resistance to chemotherapy.…”