FGF19-FGFR4 axis as the inaugural target for determining the efficacy of advanced esophageal cancer treatment.

4035 Background: Advanced esophageal cancer (EC) remains a fatal stage with limited survival benefits from current treatments due to lack of specific targets. Esophageal squamous cell carcinoma (ESCC) is the most common type observed in EC cases. Studies have shown that around 40% of ESCC cases exhibit amplification of chromosome 11q13, which includes genes like FGF19, FGF3, FGF4, and CCND1. Among these, FGF19 and its receptor FGFR4 play crucial roles in cancer progression. Blocking the FGF19-FGFR4 axis could potentially disrupt tumor progression. Anlotinib, a multi-targeting tyrosine kinase inhibitor, targets VEGFR2, PDGFR, and FGFR1-4. In this study, we analyzed the next-generation sequencing (NGS) data from our cohort of advanced EC patients to identify potential therapeutic targets based on their genetic mutations. We also investigated whether FGF19 amplifications could enhance sensitivity to anlotinib-based treatments. Methods: The study was conducted as a retrospective analysis at our institution from October 2017 to August 2021. To be included in the study, patients had to be between 18 and 75 years old, have confirmed metastatic and/or recurrent EC with measurable lesions, and have detailed clinical information without any other primary tumors. We used NGS to analyze the mutation landscape in advanced EC patients. Additionally, we investigated the therapeutic effects of blocking the FGF19-FGFR4 axis by retrospectively analyzing the outcomes of advanced EC patients who received anlotinib-based treatments, which target the FGFR family. We compared overall survival (OS), progression-free survival (PFS), and best response between advanced EC patients with and without FGF19 amplifications who received anlotinib-based treatments. Results: A total of 50 patients with advanced EC (47 with squamous carcinoma and 3 with adenocarcinoma) underwent NGS testing. FGF19 amplifications were the third most common mutation, occurring in 46% of patients, following TP53 (88%) and CCND1 (48%). Among the 26 patients receiving anlotinib-based treatment, 13 (50%) had FGF19 amplifications. Patients with FGF19 amplifications had a 69.2% objective response rate (ORR) and a 100% disease control rate (DCR). None of the 13 patients with FGF19 amplifications developed progressive disease (PD). Patients with FGF19 amplifications showed significant improvements in ORR (69.2% vs. 12.5%, p=0.011) and median PFS (5.3 vs. 2.7 months, HR=0.10, 95%CI: 0.02-0.56, p=0.0015) compared to those without FGF19 amplifications. Improvements in DCR (100% vs. 75%, p=0.06) and median OS (8.7 vs. 7.2 months, HR=0.44, 95CI%: 0.12-1.59, p=0.2) were also observed, albeit not statistically significant. Conclusions: Anlotinib-based therapy showed improved clinical outcomes in patients with FGF19 amplifications. This suggests that targeting FGF19 amplifications could be a promising approach for treating advanced ESCC.