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Ref Type Abstract
Authors A. Hollebecque, M. Borad, L. Goyal, A. Schram, J.O. Park, P.A. Cassier, S.D. Kamath, D.T. Wai Meng, E. Dotan, R. Kim, V. Sahai, D. Oh, C. Liao, M. Millward, D. Roda Perez, C. Ferté, R. Blakesley, B. Wolf18, V. Subbiah, R.K. Kelley
Title 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
Journal Annals of Oncology
Vol 33
Issue Supplement 7
Date Sep 11, 2022
Abstract Text 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: 000LBA12


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 fusion cholangiocarcinoma predicted - sensitive RLY-4008 Phase Ib/II Actionable In a Phase I/II trial (ReFocus), RLY-4008 treatment resulted in an objective response rate (ORR) of 88% (15/17), a confirmed ORR of 82.4% (14/17), and a disease control rate of 100% (17/17) at the recommended Phase II dose, and an ORR of 63.2% (24/38) at all dose levels in patients with FGFR inhibitor-naive cholangiocarcinoma harboring FGFR2 fusions or rearrangements (Ann Oncol (2022) 33 (suppl_7): S808-S869; NCT04526106). detail...