RLY-4008 Shows Initial Activity With a Manageable Safety Profile in Cholangiocarcinoma


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Mitesh J. Borad, MD, highlights key additional findings from ReFocus and how RLY-4008 differs from currently available FGFR2 inhibitors.

Investigators hope to add RLY-4008, the first highly selective FGFR2 inhibitor, to the growing arsenal of treatment options for patients with cholangiocarcinoma.

Mitesh J. Borad, MD

The first highly selective FGFR2 inhibitor RLY-4008 has displayed preliminary efficacy in patients with cholangiocarcinoma and has the potential to establish another agent in the treatment paradigm, according to Mitesh J. Borad, MD.

Borad presented updated results from the phase 1/2 ReFocus trial (NCT04526106) with the agent at the 2023 ASCO Annual Meeting. At the January 30, 2023, data cutoff, findings showed that patients with FGFR inhibitor–naïve cholangiocarcinoma harboring fusions or rearrangements (n = 25) who received RLY-4008 achieved an overall response rate (ORR) of 52% (95% CI, 31.3%-72.2%) across all doses examined. Additionally, the ORR among patients with FGFR inhibitor–refractory cholangiocarcinoma harboring fusions or rearrangements (n = 50) was 14% (95% CI, 5.8%-26.7%) across all doses examined. The median durations of response (DOR) were 8.2 months (range, 5.6-not available [NA]) and 5.6 months (range, 3.7-NA), respectively.

In the overall safety population (n = 116), the most common any-grade treatment-related adverse effects (TRAEs) were palmar-plantar erythrodysaesthesia (57%), stomatitis (57%), and nail toxicities (53%). Three patients discontinued treatment due to adverse effects (AEs).

“FGFR2-selective inhibitors such as RLY-4008 have [demonstrated] promising initial efficacy and distinct safety profiles,” Borad said in an interview with OncLive® during the 2023 ASCO Annual Meeting. “Phase 2 data on these agents will be eagerly awaited to see where they could have a role in the current clinical landscape.”

In the interview, Borad, an oncologist at Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, highlighted key additional findings from ReFocus and how RLY-4008 differs from currently available FGFR2 inhibitors.

OncLive: What is the mechanism of action of RLY-4008 and what were key inclusion criteria for patients to receive the agent in ReFocus?

Borad: RLY-4008 is a third-generation FGFR2 inhibitor. It uses molecular dynamics-based methods to affect a portion of the ATP pocket not affected by other first- and second-generation inhibitors.

[ReFocus] is an ongoing phase 1/2 study and results were presented from the dose-escalation portion, which involved a variety of solid tumors that [were] refractory to standard therapies. Predominantly, these were patients with cholangiocarcinoma. Tumors had to have alterations in FGFR2, including fusions, rearrangements, mutations, or amplifications, and most patients had [received] multiple prior lines of therapy.

How would you characterize the activity of RLY-4008 based on the efficacy data that you presented during the 2023 ASCO Annual Meeting?

We presented efficacy data in patients with cholangiocarcinoma. We divided [patients] into several categories, [including] those who had fusions or rearrangements and those who had mutations; among patients who had fusions or rearrangements, there were those who were pretreated with FGFR inhibitors and those who did not receive prior treatment with FGFR inhibitors.

[In ReFocus] there were 3 dosing schedules: daily, twice daily, and daily for 3 weeks followed by a week off. Based on pharmacokinetic, pharmacodynamic, safety, and efficacy data, the 70 mg daily schedule was selected for further evaluation. The efficacy was reported for patients who received 70 mg or more [of RLY-4008] vs those who got less than 70 mg.

Patients who had fusions or rearrangements that were FGFR2 inhibitor naïve [n = 11] and were treated with at least 70 mg of the drug daily [achieved] an ORR of 73%, albeit [these results were] from small numbers. In patients who received below 70 mg, the ORR was 36%. Given that we’re proceeding with the 70-mg daily schedule, this is quite an impressive response rate. These responses are also durable. In the 70-mg and above group, the median DOR was 11.2 months; the 6-month progression free survival [PFS] and disease control rate [DCR] were both 100%.

Patients who are FGFR inhibitor pretreated are a very difficult group of patients [to treat] because they have lots of resistance mechanisms and don’t really have any therapies available to them. It’s a significant unmet need, [but] there was still activity in these patients [n = 14 who received the higher dose]; the ORR was 21%, the median DOR was a bit shorter, as would be expected, at 5.6 months, the 6-months PFS [rate] was 43%, and the DCR was 93%. [These are] still impressive numbers given how difficult this patient population is [to find] effective treatments for.

In patients who had mutations, this was a small group of only 14 patients, the ORR was 29% [across all dose levels]. These were a wide variety of mutations in [terms of] where they occur in the protein. As more data evolves, it may turn out that certain mutations [are associated with] a higher response rate than others.

All in all, in patients with cholangiocarcinoma who have FGFR2 alterations, the efficacy is quite impressive.

Were any safety concerns observed with RLY-4008?

The toxicity profile is somewhat more selective—these drugs don’t have FGFR1 or FGFR4 toxicities, it’s only on-target toxicity with FGFR2 [that we see]. There was no hyperphosphatemia, and diarrhea was quite limited.

Although there were some AEs, on-target effects that would be related to skin and nail effects or ocular events, the discontinuation rate of RLY-4008 in this patient population was quite low. Dose reductions and interruptions [were] required with the drug given its AE profile, but most patients could be maintained on drug, [resulting in] these durable responses thereafter.

Given that pan-FGFR inhibition has demonstrated past efficacy in cholangiocarcinoma,what could selectively inhibiting FGFR2 mean for this population in the future?

With these third-generation [FGFR2] inhibitors, we are clearly seeing a higher response rate and the DOR thus far is quite promising. We will see what emerges from the data in the ongoing phase 2 portion, which will evaluate approximately 100 patients at the recommended phase 2 dose of 70 mg daily. If this phase replicates the numbers we’ve seen thus far, or even exceeds them, this could be quite compelling evidence in terms of efficacy.

Physicians will have a choice as these drugs are made clinically available, whether to use the first- and second-generation inhibitors which have response rates in the 30% to 40% range, or to use a third-generation drug that might have a slightly different toxicity profile but potentially more efficacy if these same numbers hold up in the phase 2 studies.


Borad MJ, Schram AM, Kim RD, et al. Updated dose escalation results for ReFocus, a first-in-human study of highly selective FGFR2 inhibitor RLY-4008 in cholangiocarcinoma and other solid tumors. J Clin Oncol. 2023;41(suppl 16):4009. doi:10.1200/JCO.2023.41.16_suppl.4009

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