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

Background: The 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.

Methods: In this open-label, single-arm, phase II trial, a chemotherapy and immunotherapy combination consisting of gemcitabine 1000 mg/m², cisplatin 75 mg/m² and 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.

Results: Thirty-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.

Conclusions: Nivolumab in combination with gemcitabine and cisplatin offers promising efficacy and a manageable safety profile for patients with advanced BTCs.

Trial registration number: NCT03311789.

Keywords: immunology; oncology.

Figure 1

Trial profile. Cis, cisplatin; Gem, gemcitabine.

Figure 2

Characteristics of clinical response and survival. (A) Highest percentage change in the change in target lesion size from baseline in patients from cohort A and cohort B; horizontal dotted lines denote a 30% decrease and 20% increase, indicating objective response and progressive disease, respectively, as per RECIST version 1.1. (B) Percentage change in target lesion tumor size from baseline over time for all evaluable patients, defined as those with baseline tumor assessments and at least one post-treatment assessment. The upper horizontal dotted line indicates disease progression at a 20% increase in the size of target lesions, and the lower dotted line represents an objective response at a 30% decrease in the size of target lesions. (C) Time to response and duration of response in patients from cohort A and cohort B. (D) Kaplan-Meier curves of investigator-assessed progression-free survival in all evaluable patients (upper left). Kaplan-Meier curves of investigator-assessed overall survival in all evaluable patients (upper right). Comparison of the median progression-free survival (mPFS) between cohort A and cohort B (low left). Comparison of the median overall survival (mOS) between cohort A and cohort B (low right). RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 3

Biomarkers for response and prognosis. (A) Correlation of TMB, TNB, heterogeneity, fitness and clinical response between the responding group and the non-responding group. (B) Mutated genes detected by whole-exome sequencing. (C) Kaplan-Meier curves of progression-free survival and overall survival between patients with high TNB and other levels of TNB. (D) Kaplan-Meier curves of progression-free survival of patients who had increased IFN-γ versus those who had decreased IFN-γ, patients who had increased granulysin versus those who had decreased granulysin, patients who had increased MCP-1 versus those who had decreased MCP-1, and patients who had increased sFasL versus those who had decreased sFasL. (E) Kaplan-Meier curves of overall survival of patients who had increased IFN-γ versus those who had decreased IFN-γ, patients who had increased granulysin versus those who had decreased granulysin, patients who had increased MCP-1 versus those who had decreased MCP-1, and patients who had increased sFasL versus those who had decreased sFasL. IFN-γ, interferon-γ; sFasL, soluble FasL; TMB, tumor mutational burden; TNB, tumor neoantigen burden.