In our study, patient 16 with advanced pancreatic cancer harboring a FGFR1–PDE4DIP fusion developed newly detected mutations in a residue near the gatekeeper (FGFR1 V559L/M) and in a molecular brake residue (FGFR1 N546K), standing as the first report of clinical on-target resistance to an FGFR inhibitor in an FGFR1-altered tumor or in pancreatic cancer to our knowledge. The gene discussed is FGFR1; the disease is familial pancreatic carcinoma.