Lenvatinib enhances the response of biliary tract cancer to anti-HER2 therapy

Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed or amplified in biliary tract cancer (BTC). Although NCCN clinical practice guidelines recommend HER2-targeted agents as subsequent-line therapy, drug resistance often restricts the clinical benefits of existing regimens. Here, we demonstrate that HER2 inhibitors have heterogeneous effects on the proliferation of BTC cells. Further bioinformatic analysis and functional experimental validation revealed that HER2 inhibitors significantly activated fibroblast growth factor receptor (FGFR) signalling pathway in HER2^high BTC. Notably, the combination of lenvatinib and a HER2 inhibitor exerted potent antiproliferative effects on HER2^high BTC models both in vitro and in vivo. In the clinical cohort, the combination therapy achieved an objective response rate (ORR) of 58.1% and a disease control rate (DCR) of 86.0%. The median progression-free survival (mPFS) was 11.27 months, and the median overall survival (mOS) reached 19.50 months. For patients with HER2^high expression, the ORR and mOS were 71.4% and 27.67 months, respectively. The overall safety profile was manageable, with no treatment-related deaths observed. These findings demonstrate that the activation of FGFR signalling confers resistance to HER2 inhibitors in HER2^high BTC. The combination of a HER2 inhibitor with lenvatinib, particularly when combined with immune checkpoint inhibitors, has exhibited both promising antitumour responses and good tolerability in patients with advanced BTC.