Our results stimulate hypotheses for exploratory studies that could guide the optimal inclusion of lenvatinib in the treatment algorithm of FGFR2-driven CCA, such as to compare the appearance of kinase resistance mutations during the treatment with lenvatinib or specific-FGFR inhibiting TKIs by repeated liquid biopsies or therapy responses despite the presence of resistance-mediating mutations. The gene discussed is FGFR2; the disease is cholangiocarcinoma.