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INTRODUCTION: Oncogenic FGFR2 alterations (fusions/rearrangements, amplifications, mutations) are key drivers in cholangiocarcinoma (CCA) and multiple solid tumors. Current pan-FGFR inhibitor (FGFRi) therapy is limited by off-isoform toxicity and acquired FGFR2 kinase domain resistance mutations. RLY-4008 is a highly selective and potent oral inhibitor designed to target both FGFR2 driver and resistance mutations. We initiated a first-in-human study in advanced solid tumors patients (pts) to define the safety, pharmacokinetics (PK) and efficacy of RLY-4008 (NCT04526106). METHODS: Adult pts received RLY-4008 QD or BID on a 4-week cycle following a BOIN escalation design. Adverse events (AEs), PK, ctDNA and anti-tumor activity (RECIST 1.1) were assessed. RESULTS: As of 16AUG21, 45 pts (35 CCA; 10 other) have been treated with RLY-4008 at total daily doses of 30-200 mg (18 pts BID; 27 pts QD). 44 pts had oncogenic FGFR2 alterations (26 fusions/13 mutations/5 amplifications). The median number of prior anti-neoplastic therapies was 3 (range 1-15). 94% (33/35) of CCA pts had prior chemotherapy and 69% (24/35) had prior FGFRi. 56% (9/16) CCA pts with prior FGFRi and evaluable ctDNA had ≥1 FGFR2 resistance mutation at baseline, most commonly at positions 549 (8/9), 617 (3/9), or 564 (2/9). RLY-4008 had rapid absorption (Tmax 1-7h), half-life to support QD dosing (18-34 h), dose-dependent exposure (AUC; Cmax) and predicted FGFR2 occupancy >85% across dose levels. The MTD has not been defined, and QD dose exploration continues to select the optimal biologically efficacious dose. AEs occurring in >20% of pts include stomatitis (49%), palmar-plantar erythrodysesthesia (PPE, 38%), dry mouth (29%), and nail toxicities (22%), majority of which were ≤Gr 2. 6 pts had Gr 1-2 retinopathy, which resolved in all cases. 5 AEs were considered dose limiting toxicities: 4 in BID (rash/PPE/mucositis/hyperbilirubinemia) and 1 in QD (retinopathy). No Gr 4/5 drug-related AEs were seen. 25 pts remain on treatment (range 1-37 weeks). RLY-4008 showed broad anti-tumor activity across dose levels and FGFR2 alterations with radiographic tumor reductions of ≥10% in 59% pts (19/32; -11% to -83%). Activity was seen in FGFRi-naïve, FGFR2-fusion+ CCA with PRs in 50% of pts (3/6, 2 confirmed and 1 pending confirmation; -56% to -83%). Activity was also seen in FGFRi pre-treated FGFR2-fusion+ CCA pts (N=16) with 16 SD, including 9 pts with tumor reduction ≥10% (from -12% to -35%). Of the FGFRi pre-treated FGFR2-fusion+ CCA patients with detectable FGFR2 resistance mutations in ctDNA at baseline, 78% (7/9) were undetectable at C2D1. CONCLUSION: RLY-4008 demonstrates promising safety, tolerability, and clinical activity in FGFR2-altered solid tumor pts, including those who progressed on prior FGFRi therapy. Consistent with the FGFR2-selective mechanism, minimal off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) was seen. These encouraging data validate selective targeting of FGFR2 and suggest that RLY-4008 has potential to overcome resistance to FGFRi. Citation Format: Lipika Goyal, Mitesh Borad, Vivek Subbiah, Amit Mahipal, Suneel Kamath, Kabir Mody, Robin Katie Kelley, Richard Kim, Vaibhav Sahai, Anthony El-Khoueiry, Efrat Dotan, Oleg Schmidt-Kittler, Jinshan Shen, Kai Yu Jen, Alicia Deary, Wei Guo, Mahesh Padval, Cori Ann J. Sherwin, Charles Ferte, Beni Wolf, Alison M. Schram. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-02.