76MO - 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

Background

Previous, nonselective FGFRi have validated FGFR2 f/r as a target in CCA by achieving an objective response rate (ORR) of ∼20-40% with duration of response (DOR) ∼5-9 months. However, off-target toxicity and emergence of polyclonal FGFR2 resistance limit their efficacy. RLY-4008 is the first highly selective, potent FGFR2 inhibitor designed to target both driver alterations and FGFR resistance mutations. Here we present the initial efficacy of RLY-4008 in pts with a FGFR2 f/r, FGFRi-naïve CCA.

Methods

ReFocus (RLY-4008-101), a Phase 1/2 study (NCT04526106), enrolled pts with advanced solid tumors who received RLY-4008 orally (20-200 mg QD or BID). FGFR2 f/r status was determined by local testing. Key objectives were investigator-assessed ORR per RECIST v1.1, DOR, and safety. Safety was analyzed in all dosed pts and efficacy in pts with FGFR2 f/r, FGFRi-naïve CCA with measurable disease and an opportunity for ≥2 tumor assessments to confirm response.

Results

As of 01AUG22, 38 pts with FGFR2 f/r, FGFRi naïve CCA were efficacy evaluable. Most pts received the recommended phase 2 dose (RP2D); most (68%) remain on treatment with median duration of 6 months (<0.1 - 18.5 months). Potent efficacy was observed across all doses, particularly at the RP2D with an ORR of 88% (Table). One pt treated at the RP2D had a near-complete response and subsequent tumor resection with curative intent. DOR is not yet mature, with majority of responses ongoing. Across all doses (N=195), the most common treatment-related AEs (TRAEs) were low-grade stomatitis (48%), PPE (46%), and dry mouth (31%). No grade 4/5 TRAEs were observed. Table: 76MO

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.

Clinical trial identification

NCT04526106.

Editorial acknowledgement

Legal entity responsible for the study

Relay Therapeutics.

Funding

Relay Therapeutics.

Disclosure

J.O. Park: Non-Financial Interests, Personal, Funding: BMS/Celgene, Servier, MedPacto; Financial Interests, Personal, Advisory Role: AstraZeneca, Servier, MedPacto. D.T. Wai Meng: Financial Interests, Personal, Research Grant: BMS; Financial Interests, Personal, Advisory Role: Novartis, Celgene, SIRTEX, MSD, Eisai, Ipsen, Bayer, BMS; Financial Interests, Personal, Invited Speaker: Ipsen, Eisai, BMS, Roche; Financial Interests, Personal, Other, Travel & Expenses: AstraZeneca. A. Hollebecque: Financial Interests, Personal, Advisory Board: Amgen, BMS, Basilea, Incyte, Servier, QED Therapeutics, Taiho, Relay Therapeutics. M. Borad: Financial Interests, Personal, Research Grant: Relay Therapeutics. L. Goyal: Financial Interests, Personal, Advisory Role: Alentis Therapeutics, Genentech, Exelixis, Incyte, QED Therapeutics, Servier, Sirtex, Taiho; Financial Interests, Personal, Advisory Board: Alentis, Black Diamond, H3Biomedicine, Incyte, QED Therapeutics, Servier, Sirtex, Taiho Pharmaceutical, Transthera, Kinnate; Financial Interests, Institutional, Research Grant: Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics, Servier, Taiho Oncology, LEAP Therapeutics, BMS, Nucana. A. Schram: Financial Interests, Institutional, Funding: Relay Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca, ArQule, BeiGene/Springworks, Black Diamond Therapeutics, Elevation Oncology, Kura, Lilly, Merus, Northern Biologics, Pfizer, PMV Pharma, Relay Therapeutics, Repare Therapeutics, Revolution Medicine, Surface Oncology; Financial Interests, Personal, Advisory Board: Relay Therapeutics, Mersana. P. Cassier: Financial Interests, Personal, Other, Honoraria: ITeos, Amgen, Janssen; Financial Interests, Personal, Advisory Role: OSE Immunotherapeutics; Financial Interests, Institutional, Research Grant: Bayer, GSK, Janssen, Lilly, AstraZeneca, Roche/Genentech, Merck Serono, Toray Industries, Novartis, Plexxikon, BMS, Taiho Pharmaceutical, Transgene, Innate Pharma, Loxo, Blueprint Medicines, Celgene, AbbVie, Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel & Expenses: Netris Pharma, Amgen, Merck Sharp & Dohme, Roche, Merck Serono, AstraZeneca/MedImmune. S.D. Kamath: Financial Interests, Personal, Advisory Board: Exelixis, Guardant Health, Tempus. E. Dotan: Non-Financial Interests, Personal, Funding: Relay Therapeutics; Financial Interests, Personal, Research Grant: Lilly, Pfizer, Incyte, AstraZeneca, SMP Oncology, Zymeworks, NGM Biopharmaceuticals, Ipsen, Syneos Health; Financial Interests, Personal, Advisory Role: QED, Taiho, Helsinn, Incyte, Basilea, SMP Oncology, G1 Therapeutics; Financial Interests, Personal, Invited Speaker: Pfizer. R. Kim: Financial Interests, Personal, Advisory Role: Bayer, Exelixis, Lilly, QED Therapeutics, Servier, Taiho Oncology; Financial Interests, Personal, Speaker’s Bureau: Incyte, Lilly; Financial Interests, Institutional, Research Grant: Bayer, BMS, Eisai. V. Sahai: Financial Interests, Institutional, Research Grant: Agios, BMS, Celgene, Clovis, Exelixis, Fibrogen, Incyte, Ipsen, Medimmune, Merck, Rafael; Financial Interests, Personal, Advisory Role: AstraZeneca, GlaxoSmithKline, Histosonics, Incyte, QED Therapeutics, Rafael. C. Liao: Financial Interests, Personal, Advisory Board: Transthera, QED Therapeutics; Financial Interests, Personal, Speaker’s Bureau: Incyte. M. Millward: Financial Interests, Institutional, Research Grant: Relay Therapeutics; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, The Limbic, Roche, BMS, Takeda Pharmaceuticals, Guardant Health, BeiGene, Amgen Australia, Merck, Lilly Australia; Financial Interests, Personal, Advisory Role: BMS, Roche, The Limbic; Financial Interests, Personal, Other, Travel & Expenses: AstraZeneca; Financial Interests, Personal, Other, DSMB: Novartis Pharma AG (Europe); Non-Financial Interests, Personal, Member of the Board of Directors: Melanoma and Skin Cancer Trials Australia. R. Blakesley: Financial Interests, Personal, Full or part-time Employment: Relay Therapeutics; Financial Interests, Personal, Stocks/Shares: Relay Therapeutics. B. Wolf: Financial Interests, Personal, Full or part-time Employment: Relay Therapeutics; Financial Interests, Personal, Stocks/Shares: Relay Therapeutics; Financial Interests, Personal, Leadership Role: Relay Therapeutics. V. Subbiah: Financial Interests, Personal, Research Grant: Relay Therapeutics. R.K. Kelley: Financial Interests, Institutional, Advisory Role: Agios, AstraZeneca, Ipsen; Financial Interests, Personal, Advisory Role: Exact Sciences, Kinnate; Financial Interests, Institutional, Research Grant: Agios, AstraZeneca, Bayer, BMS, Lilly, EMD Serono, Exelixis, Genentech/Roche, Ipsen, Loxo Oncology, Merck Sharp & Dohmw, QED Therapeutics, Partner Therapeutics, Relay Therapeutics, Surface Oncology; Financial Interests, Personal, Invited Speaker: Genentech/Roche. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. All other authors have declared no conflicts of interest.