lirafugratinib (RLY-4008)

P1/2, N=490, Active, not recruiting, Relay Therapeutics, Inc. | Trial completion date: Oct 2024 --> Aug 2025 | Trial primary completion date: Jun 2024 --> Sep 2024

At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and inter-patient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly-oriented treatment strategies across FGFR2-driven tumors.

P1/2, N=540, Active, not recruiting, Relay Therapeutics, Inc. | Recruiting --> Active, not recruiting

Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.

No abstract available

No abstract available

In vivo, RLY-4008 induces regression in multiple xenograft models - including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi - while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting.

These encouraging dose escalation data confirm the broad therapeutic potential of highly selective FGFR2 targeting with RLY-4008 by demonstrating encouraging initial efficacy across FGFR2-altered solid tumors and genomic alterations, with a differentiated safety profile that avoids FGFR1- and FGFR4-related toxicity. Phase 2 of ReFocus continues across solid tumors and with registrational intent in FGFRi-naïve, FGFR2 f/r CCA. Clinical trial information: NCT04526106.

Food and ESO does not have a clinically relevant effect on RLY-4008 PK in HS, indicating that RLY-4008 can be dosed with or without food and can be dosed with PPIs, H2-blockers and anti-acids in cancer patients.

Three FGFR inhibitors, pemigatinib, infigratinib and futinatinib, have recently received FDA approval for use in pre-treated patients...Promising results have also been reported with new-generation inhibitors such as RLY-4008, which may soon constitute new therapeutic options. In the case of NTRK fusion, larotrectinib and entrectinib have also demonstrated their efficacy. The objectives of this review are to clarify the specific diagnostic modalities for gene fusions and to summarize the results of the main trials and developments underway for the management of advanced CCA with gene fusions.

US enrollment began September 2020 and has expanded into Europe and Asia. Clinical trial information: NCT04526106.

Conclusions RLY-4008 is a promising next-generation inhibitor with potential to transform the treatment of FGFR2 f/r, FGFRi-naïve CCA. Pivotal testing continues in ReFocus.

"Today Foundation Medicine, Inc., a pioneer in molecular profiling for cancer, and Relay Therapeutics (Nasdaq: RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, announced a collaboration to develop FoundationOne^®CDx as a companion diagnostic for RLY-4008, the company’s investigational FGFR2 inhibitor....If the therapy and companion diagnostic are approved, FoundationOne CDx would be used to identify patients with FGFR2 fusions and select rearrangements in CCA who may be appropriate for treatment with RLY-4008."

ConclusionsIn this study, FGFR2 f/r detection using a novel fusion partner-agnostic cfDNA approach has an acceptable performance and is a feasible noninvasive option for screening CCA patients. These encouraging results suggest a utility of cfDNA in FGFR2 f/r profiling, which will be prospectively validated in the RLY-4008-101 pivotal study.

P1/2, N=440, Recruiting, Relay Therapeutics, Inc. | Phase classification: P1 --> P1/2 | N=200 --> 440

P1, N=200, Recruiting, Relay Therapeutics, Inc. | N=125 --> 200

No abstract available

We initiated a first-in-human (FIH) precision oncology study of RLY-4008 in advanced solid tumor pts with FGFR2 alterations with primary objectives to define the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) and adverse event (AE) profile of RLY-4008; key secondary objectives are to assess FGFR2 genotype in blood and tumor tissue, pharmacokinetics (PK), and anti-tumor activity. Given the approval of pan-FGFRi and the emerging importance of acquired resistance to pan-FGFRi, key exploratory objectives are measures of RLY-4008 anti-tumor activity with prior treatment (pan-FGFRi versus pan-FGFRi na ve) and baseline mutational status.

The primary endpoints are MTD/RP2D and AE profile; key secondary endpoints are FGFR2 genotype in blood and tumor tissue, PK parameters; overall response rate, and duration of response per RECIST 1.1 . US enrollment began SEP2020 and Europe/Asia start-up is underway.

P1, N=125, Recruiting, Relay Therapeutics, Inc. | Not yet recruiting --> Recruiting