Early Data from the ReFocus Trial

RLY-4008 is an oral inhibitor of fibroblast growth factor 2 (FGFR2) currently under investigation to treat patients with unresectable or metastatic cholangiocarcinoma (CCA) who have not responded to standard therapies. Previous studies of nonselective FGFR inhibitors have reinforced the use of fragmented and/or rearranged FGFR2 as a therapeutic target in patients with relevant CCA diagnoses. However, the efficacy of these nonselective FGFR inhibitors is limited by their significant off-target toxicity and the accumulation of FGFR resistance mutations in tumors over time.

The ReFocus (RLY-4008-101) clinical trial was a phase 1/2 nonrandomized parallel assignment study accepting patients with solid CCA tumors. Characterization of fragmented and/or rearranged FGFR2 was determined for each patient by local testing. Patients received oral RLY-4008 (doses ranged from 20 mg to 200 mg daily or twice daily). Primary objectives of this study included objective response rate (ORR) assessed per RECIST version 1.1 and duration of response (DOR) assessed up to 36 months following treatment. Safety and adverse events (AEs) were analyzed for all patients. Response was confirmed based on measurable disease and ≥2 tumor assessments. These early data were presented at the 2022 ESMO congress.

Currently, 38 patients (all FGFR inhibitor-naïve with fragmented and/or rearranged FGFR2) have received treatment and were evaluable for ORR, DOR, and safety. Most patients received the recommended phase 2 dose (RP2D, 70 mg daily), and 68% of these remained on the treatment (median duration, 6 months).

RLY-4008 showed potent efficacy across all doses, with an ORR of 88% at RP2D. In the cohort treated with RP2D, 1 patient demonstrated a near-complete response and was able to undergo subsequent curative tumor resection. Data collection for DOR is thus far incomplete, and research is ongoing. Treatment-related AEs have been grade ≤3 in severity; low-grade stomatitis (48%), palmar plantar erythrodysesthesia (46%), and dry mouth (31%) were most common.

Preliminary findings indicated that RLY-4008 has significant promise as a next-generation FGFR2-specific inhibitor to treat metastatic CCA in patients with fragmented and/or rearranged FGFR2 who have not received other FGFR inhibitor therapeutics. Research on this medication continues in the ReFocus trial.

Sources: Hollebecque A, Borad M, Goyal L, et al. Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial. Ann Oncol. 2022;33(suppl 7):S808-S869.

Hollebecque A, Borad M, Goyal L, et al. Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial. European Society for Medical Oncology Congress 2022. Abstract LBA12.