Abstract IA006: Clinical activity of lirafugratinib (RLY-4008), a highly selective FGFR2 inhibitor, in patients with advanced FGFR2-altered solid tumors: The ReFocus study

Abstract Background: Oncogenic FGFR2 alterations (fusions/rearrangements [f/r], amplifications, mutations) drive multiple solid tumors. Pan-FGFR inhibitors have validated FGFR2 as an actionable target in cholangiocarcinoma (CCA), however, activity has been limited by off-isoform toxicity and on-target resistance. Lirafugratinib (RLY-4008), the first highly selective FGFR2 inhibitor, was studied in ReFocus, an ongoing Phase I/II study (NCT04526106) in advanced FGFR2-altered solid tumor patients (pts). Previously, we defined the RP2D, confirmed the selective mechanism that minimizes off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea), and reported efficacy in CCA pts with FGFR2 f/r. Here, we report initial efficacy and safety from pts with solid tumors other than CCA treated at the RP2D. Methods: Pts with advanced solid tumors and FGFR2 alterations identified per local testing enrolled and received lirafugratinib orally. Key objectives were investigator-assessed objective response rate (ORR), duration of response (DOR), and safety. Efficacy was analyzed in pts with measurable disease, no prior FGFRi therapy and an opportunity for ³1 post-baseline imaging assessment. Safety was analyzed in all pts. Results: As of 09May23, 98 pts with solid tumors other than CCA (21 tumor types) were enrolled and treated at the RP2D. Fifty-three percent of pts had ³3 prior therapies; 19% had prior FGFRi therapy. Median treatment exposure was 8.3 weeks (range: 0.1–55.7). Of 79 FGFRi-naïve pts, 61 were evaluable; 18 unevaluable (1 nonmeasurable; 17 ongoing pending imaging). Twenty had f/r with an ORR of 40% (8/20, 7 confirmed/5 ongoing) and DOR from 8-50+ weeks. Twenty-seven had amplification with an ORR of 33% (9/27, 7 confirmed/5 ongoing) and DOR from 8-32+ weeks. Pts with breast (n=7), lung (n=3), and pancreatic (n=5) cancer with FGFR2 f/r or amplification had confirmed ORRs of 43%, 67%, and 40%, respectively. Response varied by mutation with ORR 14.3% (2 [N549K; C382R]/14; both confirmed, 1 ongoing) with DOR each of 40+ weeks. Most common treatment-related adverse events (TRAEs, all grades; grade 3) were stomatitis (50%; 10%), nail toxicities (44%; 4%), and palmar-plantar erythema (45%; 5%). Typical off-isoform TRAEs for pan-FGFR inhibitors were uncommon, including hyperphosphatemia (16%; 0%) and diarrhea (9%; 1%). One percent of pts discontinued treatment because of TRAEs. No grade 4/5 TRAEs were observed. Conclusion: Beyond CCA, lirafugratinib demonstrates promising initial efficacy in multiple tumor types with diverse FGFR2 alterations including f/r, amplification, and select mutations. Together with lirafugratinib’s differentiated safety profile (minimal off-isoform toxicity), these efficacy data validate FGFR2 as a tumor agnostic target sensitive to selective FGFR2 inhibition. Pivotal development across solid tumors continues in Phase 2 of ReFocus. Additional/updated data will be presented at the conference. Citation Format: Alison M Schram, Vivek Subbiah, Chih-Yi (Andy) Liao, Victor Moreno, Roda Desamparados, Mariano Ponz-Sarvise, Efrat Dotan, Philippe Alexandre Cassier, Irene Moreno, Andreas Varkaris, Richard D Kim, Elena Garralda, Frans Opdam, David Tai, Antoine Italiano, Do-Youn Oh, Lipika Goyal, Elisa Fontana, Jia Liu, Myrto Boukovala, Francois Ghiringelli, Mitesh J Borad, Hani Babiker, Zhaohui Jin, Michael Millward, Jeffrey Yachnin, Suneel Deepak Kamath, Jermaine M. Coward, Changhoon Yoo, Robin Kate Kelley, Vaibhav Sahai, John Bridgewater, Christoph Springfield, Vaia Florou, Anthony El-Khoueiry, Ferry Eskens, Bruce Lin, Scott Paulson, Giuseppe Curigliano, Meredith Murphy, Alicia Deary, Fabien Ricard, Kai Yu Jen, Florence (Tianhui) Ramirez, Rick E. Blakesley, Oleg Schmidt-Kittler, Brenton G. Mar, Joon Oh Park, Antoine Hollebecque. Clinical activity of lirafugratinib (RLY-4008), a highly selective FGFR2 inhibitor, in patients with advanced FGFR2-altered solid tumors: The ReFocus study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA006.