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.

662 Background: Activating alterations in FGFR3 (most commonly S249C) occur in 15-20% of metastatic urothelial cancers (mUC) and &lt;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 .