Novel FGFR2 Inhibitor Shows Promise in Patients With Cholangiocarcinoma and an FGFR2-Fusion or Rearrangement

According to initial efficacy results of a phase 1/2 study, RLY-4008, a highly selective FGFR2 inhibitor, shows promise for FGFR inhibitor-naïve patients with cholangiocarcinoma and an FGFR2-fusion or rearrangement.

There has been success with nonselective FGFR inhibitors in cholangiocarcinoma. However, as lead investigator Antoine Hollebecque, MD, Gustave Roussy Cancer Center, Villejuif, France, and colleagues wrote, “off-target toxicity and emergence of polyclonal FGFR2 resistance limit their efficacy.”

RLY-4008 is the first highly selective, potent FGFR2-inhibitor that targets both driver alterations and resistance mutations.

The open-label ReFocus study enrolled patients with advanced cholangiocarcinoma and an FGFR2-fusion or rearrangement who had not previously been treated with an FGFR inhibitor. Phase 1 of the study was a dose escalation, evaluating doses from 20 to 200 mg of RLY-4008 administered orally, either once or twice daily. Phase 2 involved dose expansion with the recommended phase 2 dose of 70 mg RLY-4008 orally once a day, as determined by Phase 1. The primary end points were objective response rate (ORR), duration of response (DoR), and safety.

As of August 1, 2022, a total of 38 patients were efficacy-evaluable. Of those patients, 17 had received the recommended phase 2 dose. For patients across all dose levels, 68% remained on treatment, with a median treatment duration of 6 months. While potent efficacy was observed across all doses, patients who received the recommended phase 2 dose had an ORR of 88% (95% confidence interval, 63.6-98.5).

There was 1 near-complete response in a patient receiving the recommended phase 2 dose, followed by a curative-intent resection. Because the trial is ongoing, data for DoR is not yet mature, however, the ongoing responses with the recommended phase 2 dose and all dose levels are 100% and 79.2%, respectively.

Among 195 patients and across all doses, the most common treatment-related adverse events reported were low-grade stomatitis (48%), palmar plantar erythodysesthesia (46%), and dry mouth (31%). All treatment-related adverse events were grade ≤3.

“RLY-4008 is a promising next-generation inhibitor with potential to transform the treatment of FGFR2 [fusion or rearrangement], FGFR [inhibitor]-naïve [cholangiocarcinoma],” Dr Hollebecque and colleagues concluded.

Pivotal testing of RLY-4008 within the ReFocus study is ongoing.

Source:

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. Presented at ESMO Congress; September 9-13, 2022; Paris, France. Abstract LBA12.