FGFR3 V555M

Thus, KIN-3248 is a novel FGFR1-4 inhibitor whose distinct activity profile against FGFR kinase domain mutations highlights its potential for the treatment of ICC and other FGFR-driven cancers.

Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.

Patients progressed to erdafitinib (n = 14), futibatinib (n = 4) or pemigatinib (n = 3)...In patient-derived models, erdafitinib combined with pictilisib was synergic in the presence of PIK3CA E545K, while erdafitinib-gefitinib combination overcame bypass resistance mediated by EGFR activation.Conclusions We detected a high frequency of FGFR kinase domain mutations at progression to selective FGFR inhibitors in urothelial cancer. Unlike FGFR2-driven cholangiocarcinoma, polyclonality of FGFR3 kinase domain mutations does not seem to be a hallmark of FGFR-driven urothelial cancer. The identification of off-target events and the preclinical validation sustain the potential clinical applicability of combinatorial treatment strategies.

Cohort B will enroll pts with mUC and include 2 cohorts to evaluate LOXO-435 as monotherapy (B1, B2) and 1 cohort to evaluate LOXO-435 in combination with pembrolizumab (B3). Pts in cohort B1 must have progressed on or were intolerant to a prior FGFR inhibitor, and pts in cohorts B2, B3, and C1 must be FGFR inhibitor treatment naive. Dose expansion will evaluate the safety, PK/PD, and antitumor activity (per RECIST v1.1) of LOXO-435 at the RP2D.