LAUSR

Background: Alterations in the fibroblast growth factor receptor 3 (FGFR3) have been identified as oncogenic drivers in several solid tumor malignancies, including urothelial carcinoma (UC). Available pan-FGFR inhibitors target all 4 isoforms of FGFR (FGFR1 - 4) and consequently their efficacy can be limited by off-target toxicity (i.e. inhibition of other non-altered FGFR isoforms) including gastrointestinal, oral mucositis, and cutaneous/nail disorders, as well as FGFR1-mediated hyperphosphatemia. Moreover, clinical studies of pan-FGFR inhibitors have reported the development of drug resistance through acquired gatekeeper mutations (e.g. V555M and V565F) at the time of disease progression. LOXO-435 is a potent, highly isoform-selective FGFR3 inhibitor that is designed to preserve activity in the setting of gatekeeper resistance mutations. Preclinically, LOXO-435 has demonstrated potent in vitro and in vivo activity as a selective inhibitor of both wild-type and oncogenically activated FGFR3, including FGFR3 fusions, point mutations, and acquired gatekeeper resistance mutations without evidence of FGFR1-mediated hyperphosphatemia. Methods: LOXO-FG3-22001 is a multicenter, open-label, first-in-human phase 1a/b study of LOXO-435 in patients (pts) with FGFR3-altered advanced solid tumors, including metastatic UC (mUC) (NCT05614739). Eligible pts (≥ 18 years) must have an advanced or metastatic solid tumor with an FGFR3 alteration detected in tumor or ctDNA, ECOG PS of 0-1, and have received all standard therapy or have no known available options to provide benefit. The study will be conducted in 2 phases: phase 1a dose escalation and phase 1b dose expansion. Dose escalation (cohort A) will begin as a single-patient accelerated design, allowing intra-patient dose escalation, followed by the modified toxicity probability interval-2 method. Additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. Dose escalation will assess safety, PK/PD, and antitumor activity of LOXO-435 as monotherapy to determine the recommended phase 2 dose (RP2D). Dose expansion will include 4 cohorts of pts with prespecified activating FGFR3 alterations. Cohort B will enroll pts with mUC and include 2 cohorts to evaluate LOXO-435 as monotherapy (B1, B2) and 1 cohort to evaluate LOXO-435 in combination with pembrolizumab (B3). Cohort C will enroll pts with non-UC advanced solid tumors and will evaluate LOXO-435 as monotherapy (C1). Pts in cohort B1 must have progressed on or were intolerant to a prior FGFR inhibitor, and pts in cohorts B2, B3, and C1 must be FGFR inhibitor treatment naive. Dose expansion will evaluate the safety, PK/PD, and antitumor activity (per RECIST v1.1) of LOXO-435 at the RP2D. Citation Format: Gopa Iyer, Arlene Siefker-Radtke, Matthew Milowsky, Neal Shore, Xin Gao, Melissa A. Reimers, Noah Hahn, Rasha Cosman, Nobuaki Matsubara, Andrea Necchi, Debbie Robbrecht, Armelle Vinceneux, Enrique Grande, Jae-Lyun Lee, Tian Zhang, Tormod Guren, Ulrich M. Lauer, Michal Sarfaty, Bernhard Eigl, Syed Hussain, Xiang Zhao, Arjun V. Balar, Kaitlyn Francese, Ryan Widau, Benjamin Garmezy. A first-in-human phase 1 study of LOXO-435, a potent, highly isoform-selective FGFR3 inhibitor in advanced solid tumors with FGFR3 alterations (trial in progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT119.