Phase 3 Study of Vepugratinib and Combination Therapy in Adults with Untreated FGFR3-Altered Locally Advanced or Metastatic Urothelial Carcinoma

The primary objective of this study is to evaluate the efficacy and safety of vepugratinib in combination with enfortumab vedotin and pembrolizumab compared to a placebo and the same combination therapy in adults with untreated locally advanced or metastatic urothelial carcinoma harboring an FGFR3 genetic alteration. The investigation aims to determine the clinical benefit of adding a targeted agent to the standard regimen for this specific molecular subtype of bladder cancer. The study also includes pharmacokinetic assessments.

This clinical trial involves 306 patients, including both males and females, within the age ranges corresponding to codes 3 and 4. The study population consists of individuals diagnosed with advanced or metastatic bladder cancer. Inclusion requires the presence of urothelial cancer that is unresectable and characterized by a specific FGFR3 genetic mutation detectable in tumor or blood samples. Participants must have tumors measurable according to RECIST v1.1 criteria, maintain moderate to good physical performance status, and demonstrate adequate laboratory results. The cohort is characterized by conditions including transitional cell carcinoma, urinary bladder neoplasms, and neoplasm metastasis.

This Phase 3, randomized, double-blind, placebo-controlled study evaluates the efficacy and safety of vepugratinib in combination with enfortumab vedotin and pembrolizumab. The research is intended for adults with untreated locally advanced or metastatic urothelial carcinoma characterized by an FGFR3 genetic alteration. Participants will receive either vepugratinib or a placebo alongside the comparator therapies. The primary endpoints include overall response rate and progression-free survival as assessed by blinded independent central review. Study involvement may last up to approximately 6 years. The clinical process involves a screening period to confirm eligibility based on tumor measurement via RECIST v1.1, physical status, and laboratory results, followed by treatment and monitoring phases.

LOXO-435, also identified as (S)-4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H,1,2,3-triazol-1-yl)piperidine-1-carbonitrile, is an experimental medicinal product administered as a tablet. The oral use dosage is 400 mg.

Enfortumab vedotin is a comparator treatment administered via intravenous use at a dosage of 1.25 mg/kg.

Pembrolizumab is a comparator treatment administered via intravenous use at a dosage of 200 mg.

A placebo is utilized in the study to match the experimental treatment.

The assessment of efficacy in this study involves several primary endpoints. The overall response rate (ORR) will be evaluated during the safety lead-in phase. Additionally, progression-free survival (PFS) will be measured via blinded independent central review (BICR).