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|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|
|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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|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...|