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Novel Therapeutic Approaches to Target FGFR2 Mutations in Cholangiocarcinoma
Volume 1
Issue 1

Efficacy of RLY-4008 Signals Potential Role for Selective FGFR2 Inhibition in FGFR2-altered Cholangiocarcinoma

Mitesh J. Borad, MD, discusses the design and methodology of the ReFocus trial, updated efficacy and safety data for RLY-4008 in the dose-escalation study, and how selective FGFR2 inhibition has the potential to shift the treatment landscape in cholangiocarcinoma.

Mitesh J. Borad, MD

Mitesh J. Borad, MD

The preliminary clinical activity and durability observed with the first-in-class, highly selective FGFR2 inhibitor RLY-4008 in patients with FGFR2-altered cholangiocarcinoma, including those previously treated with an FGFR inhibitor, indicate that selective and irreversible FGFR2 inhibition may be a promising new strategy in this space, according to Mitesh J. Borad, MD.

Updated findings from the dose-escalation portion of the phase 1/2 ReFocus trial (NCT04526106) presented at the 2023 ASCO Annual Meeting showed that treatment with RLY-4008 at 70 mg daily or higher produced an overall response rate (ORR) of 73% in FGFR inhibitor–naïve patients with FGFR2 fusion–positive cholangiocarcinoma (n = 11). Moreover, doses of at least 70 mg elicited an ORR of 21% in FGFR inhibitor–pretreated patients with this subtype (n = 14). In patients treated with doses of less than 70 mg in the FGFR inhibitor–naïve (n = 14) and –pretreated (n = 36) populations, the ORRS were 36% and 11%, respectively.

The recommended phase 2 dose (RP2D) was determined to be 70 mg daily. The agent had a favorable pharmacokinetics/pharmacodynamic profile at the RP2D, with continuous target inhibition of 96% or greater. Regarding safety, RLY-4008 produced mostly low-grade adverse effects (AEs) that were on target and predominantly reversible with proper management.

The ongoing phase 2 portion of ReFocus will evaluate the efficacy of RLY-4008 at the RP2D with registrational intent, and investigators aim to complete enrollment by the second half of 2023.

“FGFR2-selective inhibitors like RLY-4008 have promising initial efficacy and distinct safety profiles,” said Borad, an oncologist in the Department of Medical Oncology at the Mayo Clinic in Phoenix, Arizona. “Phase 2 data on these agents will be eagerly awaited to see where they could [fit into] the current clinical landscape.”

In an interview with OncLive®, Borad discussed the design and methodology of the ReFocus trial, updated efficacy and safety data for RLY-4008 in the dose-escalation study, and how selective FGFR2 inhibition has the potential to shift the treatment landscape in cholangiocarcinoma.

OncLive: Could you expand on the unique mechanism of action of RLY-4008 and what differentiates it from other FGFR2 inhibitors??

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 the other inhibitors from the first and second generations.

What were the inclusion criteria for the ReFocus trial?

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

What key efficacy data from the dose escalation portion of this trial were presented at this year’s ASCO meeting?

At the 2023 ASCO Annual Meeting, we presented efficacy data predominantly in [patients with] cholangiocarcinoma. We can divide these patients into several categories: patients who have [FGFR2] fusions or rearrangements, and patients who have [FGFR2] mutations. Within those patients that have fusions or rearrangements, you would have patients pretreated with FGFR inhibitors and patients who had not received prior FGFR inhibitors.

The dose that was selected for phase 2 studies, which are ongoing at this time, was 70 mg daily. There were 3 [dose] schedules: a daily schedule, a twice-a-day schedule, and then daily dosing for a 3-weeks-on/1 -week-off schedule.

Based on pharmacokinetic, pharmacodynamic, safety, and efficacy data, the 70 mg daily schedule has been selected for further evaluation. The efficacy was reported as those patients who received 70 mg or more [of RLY-4008], vs those patients who received less than 70 mg.

In patients who had [FGFR2] fusions or rearrangements and were FGFR2 inhibitor–naïve, in the group that got at least 70 mg daily [n = 11], the response rate was 73%. In patients who [were given less than] 70 mg [n = 14], the ORR was [36%]. There's a demarcation at 70 mg [dose]. 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 daily [and above population], the duration of response [DOR] was [11.2] months, and the 6-month progression free survival [PFS] rate and disease control rate [DCR] were both 100%.

For patients who were FGFR inhibitor pretreated, [this] is a very difficult group of patients [to treat], because they have lots of resistance mechanisms and don't have many therapies available to them, so this is a significant unmet need. There was still activity [with RLY-4008]. In these patients, the ORR was 21% [for those given at least 70 mg of RLY-4008]. The DOR was a bit shorter [than the FGFR inhibitor–naïve cohort] at 5.6 months, as would be expected. The 6-month PFS was [43%], and DCR was [93%]. [These were] still impressive numbers given how difficult it is [to find effective subsequent treatments] for this patient population.

A small group of 14 patients had FGFR2 mutations. Two patients had [FGFR2] amplifications, which were not reported. In those patients who had FGFR2 mutations, the ORR was 29% [for all doses of RLY-4008]. This [cohort encompassed] a wide variety of [FGFR2] mutations and where they occur in the protein. As more data evolve, we may see that certain mutations [may be associated with] higher response rates than others.

All in all, in patients with cholangiocarcinoma who have FGFR2 alterations, the efficacy [of RLY-4008] is quite impressive.

What should be known about RLY-4008’s safety profile?

The toxicity profile is also somewhat more selective. [Selective FGFR2 inhibitors] do not have FGFR1 or FGFR4 toxicity; there is only on-target toxicity with FGFR2. [In these findings from ReFocus], there was no hyperphosphatemia, and diarrhea was limited.

Although there were some on-target AEs, which [include] skin, nail, or ocular AEs, the discontinuation rate of the drug in this patient population was quite low. Only [2.6%] of [all] patients discontinued the drug due to toxicity. [There were] dose reductions and interruptions required with the drug, given its AE profile, but most patients could be maintained on the drug thereafter to [achieve] durable responses.

Given the past efficacy demonstrated by pan-FGFR inhibitors in patients with cholangiocarcinoma, how could selective FGFR2 inhibition mean for this population?

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

If these drugs are made clinically available, physicians will [be able to choose] whether to use the first- and second-generation inhibitors, which [produce] response rates more in the 30% to 40% range, or a third-generation drug [that] might have a slightly different toxicity profile but potentially more efficacy.

Disclosures: Dr Borad reports receiving research funding from Relay Therapeutics.


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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