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FGFR2 Inhibitor Under Study in Cholangiocarcinoma

By: Julia Fiederlein
Posted: Friday, October 7, 2022

Treatment with RLY-4008 demonstrated antitumor activity in patients with FGFR inhibitor–naive, FGFR2 gene fusion or rearrangement–positive cholangiocarcinoma, according to Antoine Hollebecque, MD, of Gustave Roussy, Villejuif, France, and colleagues. The initial efficacy analysis of the phase I/II ReFocus trial, which was presented during the European Society for Medical Oncology (ESMO) Congress 2022 (Abstract LBA12), suggested this next-generation FGFR2 inhibitor has the potential to transform the treatment paradigm in this setting.

“Off-target toxicity and emergence of polyclonal FGFR2 resistance limit [the efficacy of previous, nonselective FGFR inhibitors],” the investigators commented. “RLY-4008 is the first highly selective, potent FGFR2 inhibitor designed to target both driver alterations and FGFR resistance mutations.”

Patients with advanced solid tumors who received oral RLY-4008 at doses ranging from 20 to 200 mg once or twice daily were enrolled. Safety was analyzed in all patients (n = 195), and efficacy was evaluated in those with FGFR inhibitor–naive, FGFR2 gene fusion or rearrangement–positive cholangiocarcinoma with measurable disease and an opportunity for at least two tumor assessments to confirm response (n = 38). A recommended phase II dose of 70 mg daily was established, and it was administered to 17 of the efficacy-evaluable patients.

The objective response rate was 88.2% with the recommended phase II dose and 63.2% across all dose levels. One patient treated with the recommended phase II dose achieved a near-complete response and underwent subsequent tumor resection with curative intent. The study remains immature for the duration of response analysis; according to the investigators, the majority of responses are ongoing.

Across all dose levels, low-grade stomatitis (48%), palmar-plantar erythrodysethesia (46%), and dry mouth (31%) were the most frequently reported treatment-related adverse events. No grade 4 or 5 treatment-related adverse events were observed.

Disclosure: For full disclosures of the study authors, visit

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