Dr. Borad on the Use of Next-Generation FGFR Inhibitors in Cholangiocarcinoma and Urothelial Carcinoma

Mitesh J. Borad, MD, oncologist, Department of Medical Oncology, Mayo Clinic Comprehensive Cancer Center, discusses the unique mechanism of action of next-generation FGFR inhibitors like KIN-3248 and their potential effect on patient outcomes in cholangiocarcinoma and urothelial cancer.

The next-generation FGFR inhibitor KIN-3248 is of particular interest for intrahepatic cholangiocarcinoma and urothelial cancer, as FGFR alterations are common in these tumor types, Borad continues. The safety and preliminary efficacy of this agent is under investigation in the phase 1 KN-4802 trial (NCT05242822) of advanced solid tumors harboring FGFR2 and FGFR3 gene alterations. KN-4802 is a two-part study and consists of a dose-escalation followed by a planned dose-expansion cohort. The trial is open to enrollment and is expected to enroll approximately 120 patients.

Researchers hope that these early phase trials will provide a broader array of targeted treatments for patients with these tumor types and address several limitations associated with early FGFR inhibitors.

Acquired resistance to FGFR inhibitors often results from on-target polyclonal mutations, which prevents the agents from binding to the ATP active site and inhibiting the protein, Borad begins. Unlike early FGFR inhibitors, next-generation FGFR inhibitors are designed to bind at non-mutated sites in the ATP-binding pocket, thereby successfully inhibiting the protein, he explains.

Currently, around 30% of patients achieve responses for up to 6 or 7 months with available inhibitors. Future-generation inhibitors may increase the proportion and durability of these responses.

Moreover, current FGFR inhibitors are associated with increased toxicities, as these agents can bind to FGFR1, FGFR2, and FGFR3 receptors. Targeting FGFR alterations that are not related to the specific tumor mutation will not confer resistance and instead leads to off-target effects. Therefore, more selective agents are needed to reduce these toxicities in patients with specific alterations or fusions, Borad concludes.