A first-in-human phase 1 study of LY3866288 (LOXO-435), a potent, highly isoform-selective FGFR3 inhibitor (FGFR3i) in advanced solid tumors with <i>FGFR3</i> alterations: Initial results from FORAGER-1.
Gopa Iyer, Hiromichi Ebi, Natalie Cook, Xin Gao, Shigehisa Kitano, Nobuaki Matsubara, Melissa A. Reimers, Arlene O. Siefker‐Radtke, Miso Kim, Matthew D. Galsky, Debbie Robbrecht, Jun Guo, Bernhard J. Eigl, Clare Schaverien, Brent D. Butts, Eunice Yuen, Sylwia Szymczak, Xiang Zhao, Ryan C. Widau, Alexandra Drakaki
Abstract
662 Background: Activating alterations in FGFR3 (most commonly S249C) occur in 15-20% of metastatic urothelial cancers (mUC) and <5% in other solid tumors. Erdafitinib, a pan FGFR1-4 inhibitor, improves survival in 2L FGFR3 -altered mUC but has dose limiting toxicities (DLTs) driven by off-target FGFR1/2/4 inhibition. LY3866288 is an oral, potent, isoform-selective, small molecule FGFR3i designed to limit off-target toxicities with preserved activity against acquired FGFR3 resistance mutations. Here we report initial clinical data from the phase 1 dose escalation cohort of LY3866288in FGFR3 -altered advanced solid tumors. Methods: Adults with advanced or metastatic solid tumors with an FGFR3 or FGFR3 ligand alteration (tumor or blood) that progressed on available standard therapies, ECOG PS ≤1, and RECIST v1.1 evaluable (including non-measurable) disease were eligible. Dose escalation used a single-patient accelerated design followed by mTPI-2 method. Key endpoints were safety, PK, and antitumor activity. Serial plasma samples were collected for ctDNA analysis. Results: As of 27 Aug 2024, 101 patients (pts) were treated at 10 dose levels (DLs) of LY3866288 (6 mg QD – 400 mg BID). Median age was 67 (range, 26-93), 69% ECOG PS 1, and 70% had mUC. Median lines of prior therapy was 3 (range, 1-9), including prior FGFRi in 23%. LY3866288 consistently demonstrated trough concentrations that exceeded IC 90 for FGFR3 S249C at DLs ≥200 mg BID. No significant differences in exposures were observed in pts with moderate renal insufficiency (eGFR 30-49 ml/min). No DLT was observed at any DL. At DLs ≥200 mg BID, the most common treatment-emergent AEs (TEAEs) were diarrhea (67%), hyperphosphatemia (28%), fatigue (23%), increased ALT (22%), and AST (22%); most (68%) TEAEs were grade 1/2. TEAEs associated with poor tolerance and compliance to erdafitinib (retinopathy, onycholysis, and hand-foot syndrome) were ≤5% and low grade. Treatment-related AEs (TRAEs) led to dose reduction in 5% of pts and none were associated with discontinuation. In mUC pts with an activating mutation/fusion dosed at ≥200 mg BID, the objective response rate (ORR) was 42% (14/33; 10 confirmed as of 6 Sep 2024, 4 ongoing and pending confirmation); responses were observed in both mutations (Y373C, S249C, R248C, S371C) and fusions (TACC3). In mUC pts previously treated with an FGFRi, the ORR was 45% (5/11). One pt each with NSCLC (S249C) and biliary tract cancer (TACC3) also achieved a PR. 14/16 PRs (88%) are ongoing. Decreases in FGFR3 ctDNA VAF occurred in 12/13 pts (92%) with available results at cycle 2 or 3, of which 8 achieved clearance (5 with PR; 3 with SD). Conclusions: LY3866288 is well-tolerated with robust clinical activity at multiple DLs, including in erdafitinib refractory mUC. Randomized dose optimization is ongoing and updated results will be presented. Clinical trial information: NCT05614739 .