A Phase 1 Study of KIN-3248, an irreversible small molecule pan-FGFR inhibitor, in Patients with Advanced FGFR 2/3 Driven Solid Tumors.

BACKGROUND: Despite efficacy of approved FGFR inhibitors, emergence of polyclonal secondary mutations in the FGFR kinase domain leads to acquired resistance. KIN-3248 is a selective, irreversible, orally bioavailable, small molecule inhibitor of FGFR1-4 that blocks both primary oncogenic and secondary kinase domain resistance FGFR alterations.

MATERIALS AND METHODS: A first-in-human, Phase 1 study of KIN-3248 was conducted in advanced solid tumors patients harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822). The primary objective was determination of maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D). Secondary and exploratory objectives included antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and molecular response by circulating tumor DNA (ctDNA) clearance.

RESULTS: Fifty-four patients received doses ranging from 5mg to 50mg orally daily across 6 cohorts. Intrahepatic cholangiocarcinoma (48.1%), gastric (9.3%) and urothelial (7.4%) were the most common tumors. Tumors harbored FGFR2 (68.5%) or FGFR3 (31.5%) alterations-23 (42.6%) received prior FGFR inhibitors. One DLT (hypersensitivity) occurred in Cohort 1 (5 mg). Treatment-related, adverse events included hyperphosphatemia, diarrhea, and stomatitis. The MTD/RP2D was not established. Exposure was dose proportional and concordant with hyperphosphatemia. Five partial responses were observed; 4 in FGFR inhibitor naïve and 1 in FGFR pretreated patients. Pretreatment ctDNA profiling confirmed FGFR2/3 alterations in 63.3% of cases and clearance at Cycle 2 associated with radiographic response.

CONCLUSION: The trial was terminated early for commercial considerations; therefore, RP2D was not established. Preliminary clinical data suggest that KIN-3248 is a safe, oral FGFR1-4 inhibitor with favorable PK parameters, though further dose escalation was required to nominate the MTD/RP2D.