FGFR2 Inhibitor RLY-4008 Appears Durable, Tolerable in Cholangiocarcinoma

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Suneel Kamath, MD, discusses the current challenges of treating patients with cholangiocarcinoma, the need for more tolerable therapies in this population, and how the significant ORRs and impressive safety profile seen so far with RLY-4008 in the ReFocus trial are indicative of this agent’s efficacy and durability in FGFR2-rearranged cholangiocarcinoma.

RLY-4008, a highly selective FGFR2 inhibitor, has demonstrated promising efficacy in patients with FGFR2-altered cholangiocarcinoma, while sparing patients the adverse effects (AEs) typically seen with pan-FGFR inhibitors, according to Suneel Kamath, MD.

The phase 1/2 ReFocus trial (NCT04526106) is investigating RLY-4008 in patients with advanced solid tumors with FGFR2 alterations, including those with FGFR inhibitor–naïve cholangiocarcinoma. Initial efficacy data from this trial, which were presented at the 2022 ESMO Congress, showed that at the recommended phase 2 dose of 70 mg daily, the agent elicited an overall response rate (ORR) of 88.2% (95% CI, 63.6%-98.5%) and a confirmed ORR of 82.4% (95% CI, 56.6%-96.2%). Additionally, among patients who received all dose levels of the drug, the ORR and confirmed ORR were 63.2% (95% CI, 46.0%-78.2%) and 57.9% (95% CI, 40.8%-73.7%), respectively.1

“This response has been durable, as some of the patients are nearing 2 years on therapy,” Kamath said in an interview with OncLive®. “To have an agent [with the potential to] work for that long that also has a favorable safety profile is truly a win all around.”

In the interview, Kamath discussed the current challenges of treating patients with cholangiocarcinoma, emphasized the need for more tolerable therapies in this population, and highlighted how the significant ORRs and impressive safety profile seen so far with RLY-4008 in the ReFocus trial are indicative of this agent’s efficacy and durability in FGFR2-rearranged cholangiocarcinoma.

Kamath is an assistant professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Ohio.

OncLive®: What are some of the difficulties of treating patients with cholangiocarcinoma given the current treatment armamentarium?

Kamath: The challenges in the advanced metastatic setting for biliary tract cancers are both identifying the patients who have precision targeted therapy options and maximizing the efficacy we can get out of those [options] for patients with genomically actionable alterations.

How prevalent are FGFR1 and FGFR2 mutations within cholangiocarcinoma, and what challenges arise when treating these specific populations?

FGFR2 fusions and rearrangements, which are the most sensitive of the FGFR2 alterations, are present in about 10% to 15% of intrahepatic cholangiocarcinoma. That’s by far the highest frequency. Fortunately, it’s also the majority of what we see in the United States. The rates [of these mutations] are significantly lower in extrahepatic cholangiocarcinoma and gallbladder cancers, on the order of a few percent.

The main challenges with the existing landscape [reside in our] 3 pan-FGFR inhibitors. They target FGFR2, but they also have significant off-isoform activity on FGFR1, FGFR3, and FGFR4. These are often where some of the undesired toxicities tend to occur.

How is RLY-4008, which is selective for FGFR2, beneficial in curbing some of the AEs that arise with agents that affect FGFR1, FGFR3, and FGFR4?

RLY-4008 was designed such that its IC50 is significantly more selective for FGFR2. That could have 2 potential advantages. One, from an AE standpoint, we expected to see significantly reduced rates of the electrolyte derangements with phosphorus and calcium that are often seen with pan-FGFR inhibitors, hyperphosphatemia being the predominant one. [Additionally, we expected to see reduced rates of diarrhea, which] can also be an issue with the pan-FGFR inhibitors. We expected that this agent would be better in that regard.

We also hoped that this agent would be more effective because of its greater selectivity. We expected that maybe the efficacy would be better in patients who have fusion or relocation events. [We also wanted to] see some responses in patients who have other alterations like amplifications or mutations in FGFR2, because the existing pan-FGFR inhibitors haven’t shown much activity outside of patients who have fusions or rearrangements.

What was the design of the ReFocus trial, and what were some of the key inclusion criteria?

This was a 2-part phase 1 and then phase 2 expansion trial design. It was open for any patients with advanced or metastatic solid tumors, [including] cholangiocarcinoma, harboring any alteration in FGFR2, beyond just fusions and translocations. Initially, we went through the [Bayesian Optimal Interval Design]and then had some expansion at the expected recommended phase 2 dose. We have now established the recommended phase 2 dose to be 70 mg once daily.

Now, we’ve moved on to the expansion phase of the study, which has [4 cholangiocarcinoma] cohorts. [The first cohort consists of] patients with cholangiocarcinoma with FGFR2 fusions who have gotten prior FGFR inhibitors in the past. [The second cohort is made up of] patients who have FGFR2 fusions who have [received prior chemotherapy but have] not gotten FGFR inhibitors. [The third cohort consists of patients with FGFR2 fusions who have not received prior chemotherapy or prior FGFR inhibitors.] The fourth cohort is the exploratory arm looking at patients who have FGFR2 mutations or amplifications and not typical fusion or rearrangement events. There will also be further expansion cohorts looking at all solid tumors with general FGFR2 alterations.

What key efficacy findings from ReFocus were presented at ESMO?

The data are early but are certainly exciting. Data were presented from all patients included in the study [who had received the agent at] all dose levels and those who were treated at the recommended phase 2 dose. Among the 38 patients who were treated at any dose, we found an ORR of 63.2% and a disease control rate of 94.7%. This cohort included a few patients who were treated at low doses, which we’ve since learned probably aren’t high enough to be effective.

Looking closely at just the 17 patients who were treated at the recommended phase 2 dose, we saw an ORR of 88.2% and a disease control rate of 100%. Thinking about that in context, compared with other trials looking at pemigatinib [Pemazyre], futibatinib [Lytgobi], or infigratinib [Truseltiq], the response rates here are substantially higher. [The response rates in other trials are] typically in the 25% to 45% range, and [the data with RLY-4008 are] significantly better than what we see with those [other agents]. The numbers from this trial are small, and we’ll need further confirmation.

What are the next steps for investigating this agent and evaluating its potential in a larger population?

At this point, we’re further examining this dose and expanding [enrollment] numbers to truly confirm this response. Additionally, for the patients with FGFR2 alterations who have not received prior FGFR inhibitors and who may not have received any systemic therapy in the advanced setting yet, we’re looking to see if treating them up front is more effective than our current standard regimens.

We’re also curious to see how patients who have gotten prior FGFR inhibitors will do, as [all the ReFocus data in cholangiocarcinoma so far have been in] patients who had not received FGFR inhibition in the past. We [want to see] how patients who have gotten agents like pemigatinib or futibatinib in the past [will do with RLY-4008].

What is your main message for colleagues regarding RLY-4008 and the results seen so far from ReFocus?

The ReFocus study, with this agent RLY-4008, shows a promising early signal of an extremely high response rate in an FGFR inhibitor–naïve population, [a response rate that seems] significantly better than [those seen with] existing pan-FGFR inhibitors. We have also found that from a safety standpoint, we [mitigate] all the electrolyte issues with hyperphosphatemia, hypercalcemia, and diarrhea [with RLY-4008]. Having an agent that works is great.


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. Ann Oncol. 2022;33(suppl 7):S1381. doi:10.1016/j.annonc.2022.08.006