ReFocus Validates RLY-4008 As Active Agent for FGFR2+ Cholangiocarcinoma

High response rates and encouraging durability support RLY-4008 as a transformative treatment option for patients with FGFR inhibitor–naïve cholangiocarcinoma harboring an FGFR2 fusion or rearrangement, according to data from the phase 1/2 ReFocus trial (NCT04526106).

Preliminary data presented during the 2022 ESMO Congress showed that treatment with the next-generation inhibitor elicited an objective response rate (ORR) per investigator assessment was 88.2% (95% CI, 63.6%-98.5%) among 17 patients treated with the recommended phase 2 dose (RP2D) of 70 mg orally once daily. All patients had radiographic tumor reduction at this dose level and 15 patients had ongoing responses and remain on treatment. Partial responses (PRs) were reported in 82.4% of patients, unconfirmed PRs were reported in 5.9% of patients, and stable disease (SD) was reported for 11.8% of patients, with no patients experiencing progressive disease (PD). The disease control rate (DCR) was 100% (95% CI, 80.5%-100%).

Among all patients who received RLY-4008 at dose levels ranging from 20 mg to 100 mg (n = 38), the ORR was 63.2% (95% CI, 46.0%-78.2%), with 19 patients (79.2%) having an ongoing response and 92% experiencing tumor reduction. The PR and unconfirmed PR rates were 57.9% and 5.3%, respectively; 31.6% of patients had SD and 5.3% experienced PD. The DCR was 94.7% (95% CI, 82.3%-99.4%). Twenty-six patients (68.4%) remain on treatment.

Among responders who remain on treatment, 71% had an ongoing response with a median time to response of 1.8 months. The median duration of exposure was 5.5 months (range, < 0.1 to 18.5).

“RLY-4008 is the first highly selective, irreversible inhibitor designed to target oncogenic FGFR2 driver alterations and resistance mutations,” Antoine Hollebecque, MD, said in a presentation of the data. “These results suggest that RLY-4008 has the potential to transform the cholangiocarcinoma treatment paradigm and strongly support seamless expansion of ReFocus with registrational intent.” Hollebecque is a head of the conventional hospital in the Drug Development Department at Gustave Roussy Cancer Center in Villejuif, France.

“First-line treatment with gemcitabine and cisplatin chemotherapy has significant toxicity and limited efficacy with a median progression-free survival of 6 to 8 months and an overall survival of less than 8 months,” Hollebecque explained.

FGFR2 fusions and rearrangements drive a subset of cholangiocarcinoma, including approximately 10% to 15% of intrahepatic cholangiocarcinomas, who may benefit from a pan-FGFR inhibitor. In the second line or later, pan-FGFR inhibitors such as infigratinib (Truseltiq), pemigatinib (Pemazyre), and futibatinib provide an objective response among 20% to 40% of patients, with a duration of response of 5 to 10 months, Hollebecque said, noting that resistance mechanisms and toxicities limit their benefit in this population.

“RLY-4008 is designed to target FGFR2’s unique conformational dynamics, these novel mechanisms enable potent and highly selective inhibition of FGFR2 alterations and resistance mutations,” Hollebecque said.

ReFocus is a phase 1/2 dose-escalation, dose-expansion trial of RLY-4008 in patients with FGFR2 alterations in cholangiocarcinoma or other solid tumors. The dose-escalation phase is complete, with the RP2D of 70 mg under evaluation in the ongoing phase 2 expansion phase, which was initiated in December 2021. Seven cohorts are included in the phase 2 portion based on FGFR2 alteration and prior treatment.

For patients with cholangiocarcinoma, the pivotal cohort will enroll approximately 100 patients with FGFR2 fusion–positive disease who are FGFR inhibitor naïve and who have received prior chemotherapy. Other cohorts include those with FGFR2 fusion–positive disease previously treated with an FGFR inhibitor (n = 50); FGFR2 fusion–positive disease who are treatment naïve (n = 20); and those with FGFR2-mutant or -amplified disease. The 3 remaining cohorts will enroll patients with solid tumors and FGFR2 alterations, amplifications, or mutations, with approximately 30 patients enrolled to each.

The key objectives of the phase 2 portion of the trial include ORR and DOR by independent review committee.

The efficacy analysis included patients who were FGFR inhibitor naïve and treated in the phase 1 and phase 2 portion of the study with at least 2 tumor assessments to confirm response or who discontinued treatment with fewer than 2 assessments.

Patient characteristics were well balanced between RP2D cohort and the all-dose-level cohort. The median age was 57 years (range, 36-81) and 58 years (range, 33-81), respectively. Individuals had either an ECOG performance status of 0 (53% vs 50%) or 1 (47% vs 50%). In the RP2D cohort, 41%, 47%, and 12% of patients received 1, 2, or 3 or more prior lines of therapy, respectively; these rates were 47%, 32%, and 21%, respectively, in the all-dose-level cohort. The median baseline sum of target lesions using RECIST 1.1 criteria was 57 mm (range, 10-157) and 63 mm (range, 10-216), in the RP2D and all-dose-level cohorts, respectively.

Using RECIST 1.1 criteria, investigators also reported the confirmed response data for the 2 cohorts. The confirmed ORR in the RP2D cohort was 82.4% (95% CI, 56.6%-92.6%) and was 57.9% (95% CI, 40.8%-73.7%) in the all-dose cohort.

The overall safety population included all patients who received at least 1 dose of RLY-4008; this included 195 patients at any dose level and 89 patients who received the RP2D.

“Adverse effects [AEs] are low-grade, manageable, and largely reversible,” Hollebecque said. He added that this is indicative of selective FGFR2 inhibition and the sparing of FGFR1 and FGFR4 inhibition, which are associated with toxicities such as hyperphosphatemia and diarrhea, respectively.

The most common all-grade AEs in the RP2D and all-dose cohorts were stomatitis (42% vs 48%), nail toxicities (43% vs 46%), palmar planter erythrodysesthesia syndrome (35% vs 46%), dry mouth (25% vs 31%), alopecia (26% vs 27%), dry eye (12% vs 15%), and dysgeusia (16% vs 15%). Grade 3 AEs included stomatitis (8% vs 8%), nail toxicities (2% vs 2%), and palmar planter erythrodysesthesia syndrome (8% vs 15%).

Treatment-related AEs leading to dose interruption or reduction were reported for 42% and 27% of patients, respectively, in the RP2D cohort and among 47% and 33%, respectively, in the all-dose cohort. One patient discontinued treatment at the RP2D and 2 patients discontinued treatment in the all-dose cohort due to hypersensitivity and retinal pigment detachment, both of which were resolved.

In terms of pharmacokinetics, the maximum concentration was observed after 4 hours and the effective half-life of RLY-4008 was 23 hours. Hollebecque noted that the RP2D dose provided continuous coverage of the FGFR2 target.

Pharmacodynamics data showed that serum phosphate remained normal over at time at the RP2D dose and across all dose levels. “Together these data indicate that RLY-4008 targets FGFR2 without inducing FGFR1-related hyperphosphatemia,” Hollebecque said.

“ReFocus validates this novel mechanism of action and supports expedited development [of the agent],” Hollebecque concluded.

Reference

Hollebecque A, Borad, 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. doi:10.1016/annonc/annonc1089