Initial Results of RLY-4008 in a First-in-Human Study in Patients with FGFR2-Altered CCA and Multiple Solid Tumors

Interim results of the multicenter, dose-escalation/dose-expansion study indicate that RLY-4008 is well-tolerated, demonstrating selective targeting of FGFR2 and the potential to overcome FGFR inhibitor resistance in patients with advanced CCA.

RLY-4008 is a potent, selective, oral small-molecule inhibitor of FGFR2. A global, multicenter dose-escalation/dose-expansion study (ClinicalTrials.gov Identifier: NCT04526106) evaluated the safety and tolerability of RLY-4008 in patients with advanced FGFR2-altered cholangiocarcinoma (CCA) and multiple solid tumors. Initial clinical data for RLY-4008 were reported at the virtual American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC) Molecular Targets and Cancer Therapeutics Conference, held October 7-10, 2021.

A total of 49 patients were enrolled in the phase 1 part of the study. The median participant age was 60 years; the majority of patients were female (59%), had an Eastern Cooperative Oncology Group performance status of 0 to 1 (94%), and had received ≥3 prior lines of therapy (59%). Furthermore, the majority of patients had CCA (82%), with FGFR fusions in 67% of patients, FGFR2 mutations in 25% of patients, and FGFR2 amplification in 8% of patients.

Pharmacokinetic analysis found that RLY-4008 showed ≥85% predicted median receptor occupancy across all dose levels; in contrast, pemigatinib 13.5 mg once daily achieved 76% inhibition of FGFR2 at trough concentrations. The RLY-4008 half-life of approximately 15 to 20 hours supports once-daily dosing. Maximum tolerated dose has not yet been defined per protocol; recommended phase 2 dose selection is ongoing with the once-daily dosing schedule.

The treatment-emergent adverse event (TEAE) profile of RLY-4008 was consistent with FGFR1 and FGFR4 sparing. TEAEs associated with RLY-4008 therapy are mostly low grade, including hyperphosphatemia (overall: 18%; once-daily dosing: 16%; twice-daily dosing: 24%) and diarrhea (overall: 6%; once-daily dosing: 3%; twice-daily dosing: 12%). Eye toxicity included dry eye (9%, once-daily dosing), corneal adverse events (13%, once-daily dosing), and retinopathy/retinal pigment epithelial detachment (RPED) in 7 patients (3 individuals using once-daily dosing and 4 individuals using twice-daily dosing); all events of RPED were of grade 1/2 severity, self-limiting, and resolved upon treatment interruption. Grade 3 events include palmar-plantar erythrodysesthesia syndrome, stomatitis, alanine transaminase increased, and fatigue. No grade 4/5 TEAEs were reported.

Initial efficacy results indicate that RLY-4008 exhibits encouraging antitumor activity in patients with CCA. In 6 patients with FGFR inhibitor–naïve FGFR2 fusion–positive CCA, confirmed partial responses were achieved in 3 individuals and 1 patient underwent resection with curative intent. Among FGFR inhibitor–resistant FGFR2 fusion–positive CCA, 62% (13 of 21) of patients showed tumor reduction of ≥10%. In addition, 70% (7 of 10) of the patients with FGFR2 resistance mutations at baseline had all identified resistance mutations rendered undetectable at cycle 2, day 1. Treatment is ongoing in 54% (26 of 48) of the patients, with treatment discontinuations due to progressive disease reported in 73% of patients. The duration of treatment is 4 to 45 weeks.

Source: Goyal L, Borad MJ, Subbiah V, et al. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors. Presented at: American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer Virtual International Conference on Molecular Targets and Cancer Therapeutics. October 7-10, 2021. Abstract P02-02.