Lenvatinib Plus PD-1 Blockade in Refractory or Unresectable Biliary Tract Carcinoma: Insights from Real-World Evidences

Background: Co-inhibiting angiogenesis and PD-1/PD-L1 is a promising regimen for several solid tumors; however, its role in biliary tract carcinoma (BTC) remains unclear. We sought to investigate the antitumor efficacy and toxicity of lenvatinib (an oral anti-angiogenesis drug) plus PD-1 blockade in patients with advanced BTC. Methods: Patients with advanced BTC who have treated with lenvatinib plus PD-1 blockade were involved in this study. The PD-1 inhibitors only included pembrolizumab and nivolumab. The primary outcomes of this study were the objective response rate (ORR). Biomarkers, including PD-L1 expression, tumor mutational burden (TMB) and genetic alterations, were analyzed. Findings: In total, 56 patients (29 with lenvatinib plus nivolumab, 27 with lenvatinib plus pembrolizumab) were enrolled. The ORR was 30.4%, the disease control rate was 85.7%, and the clinical benefit rate was 42.9%. The median progression-free survival (PFS) was 5.0 months (95% CI: 4.0-6.0), and the median overall survival (OS) was 11.0 months (95% CI: 6.6-15.4). For tolerability, 96.4% of the patients had adverse events (AEs), but only 19.6% of the patients experienced grade-3 AEs without grade-4/5 AEs occurring. Fatigue, hypertension and hypothyroidism were the most common AEs. Moreover, PD-L1 positive expression had higher ORR and longer PFS. Further analysis of efficacy-related factors demonstrated that patients with resected BTC could obtain longer OS. TMB was significantly higher in patients with clinical benefits, and the blood TMB evaluated by circulating-free DNA could float with the changes of target lesions. Interpretation: Lenvatinib plus PD-1 inhibitor presents an effective and safe strategy in patients with advanced BTC, especially those with PD-L1 positive expression and prior surgical resection. TMB could facilitate the identification of the underlying beneficiaries. Trial Registration: The ClinicalTrials.gov identifier of this study is NCT03892577. Funding Statement: This work was supported by grants from the International Science and Technology Cooperation Projects (2016YFE0107100 and 2015DFA30650), CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003), Beijing Natural Science Foundation (L172055), National Ten-thousand Talent Program, Beijing Science and Technology Cooperation Special Award Subsidy Project and CAMS Initiative for Innovative Medicine (CAMS-2018-I2M-3-001). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The protocol used in this study was compliant with the principles of the Declaration of Helsinki. All patients who participated in this observational trial provided written informed consent for receiving medical treatment, the collection of tumor biopsies and the comprehensive molecular profiling of the tumor and germline samples. All patients were enrolled in institutional protocols approved by the Ethics Review Committee of Peking Union Medical College Hospital (Beijing, China) (reference no. JS-1391).