ASCO GU 2022: Adjuvant Infigratinib As Targeted Therapy for Patients With Muscle-Invasive Urothelial Carcinoma Harboring Susceptible FGFR3 Genetic Alterations: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial (PROOF 302)

(UroToday.com) On the second day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 Dr. Cole presented the rationale and design of the PROOF 302 trial assessing adjuvant infigratinib among patients with muscle-invasive urothelial carcinoma harboring susceptible FGFR3 genetic alterations during the in Trials in Progress Poster Session B.

Radical surgery is a standard of care and the mainstay of treatment for muscle-invasive urothelial carcinoma, whether of the upper tract urothelial cancer (UTUC; radical nephroureterectomy) and urothelial bladder cancer (UBC; radical cystectomy). However, even when surgery is combined with cisplatin‐based chemotherapy in the neoadjuvant and adjuvant settings, recurrence rates are high. Further, a large proportion of patients are ineligible for, do not respond to, or refuse cisplatin-based chemotherapy because of toxicity concerns.

Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in 20-40% of patients with muscle-invasive UTUC, and approximately 20% of patients with invasive UBC. Infigratinib (BGJ398) is an ATP-competitive FGFR1–3 selective oral tyrosine kinase inhibitor that has demonstrated clinical activity and tolerability in patients with advanced/metastatic urothelial carcinoma (UC) harboring susceptible FGFR3 alterations.

PROOF 302 is a global, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (NCT04197986) designed to investigate the efficacy and safety of adjuvant infigratinib in patients with high-risk, muscle-invasive UC (85% UTUC) and susceptible FGFR3 alterations. The PROOF 302 trial is enrolling patients with high-risk, muscle-invasive UTUC (85%) or UBC (15%) with susceptible FGFR3 alterations (mutations, gene fusions or rearrangements) confirmed by FoundationOne CDx test. Patients have to be enrolled within 120 days following nephroureterectomy, distal ureterectomy, or cystectomy. The study protocol was amended to include patients with carcinoma in situ at surgical margins and those who refuse cisplatin-based chemotherapy (in addition to pts allowed to enroll if ineligible for perioperative cisplatin-based chemotherapy).

To be eligible for inclusion, patients had to not have evidence of metastatic disease and have either disease stage ≥ypT2 and/or yN+ after cisplatin-based neoadjuvant chemotherapy or ≥pT2 pN0–2 or pN+ (UTUC); and ≥pT3 or pN+ (UBC) if not treated with cisplatin-based neoadjuvant chemotherapy.

Patients are randomized in a 1:1 fashion to receive oral infigratinib 125 mg or placebo QD on days 1–21 of a 28-day cycle for up to 52 weeks (13 cycles) or until recurrence, unacceptable toxicity, or death.

The primary endpoint is centrally reviewed disease-free survival (DFS) analyzed via stratified log-rank test and Cox model (hazard ratio) while a number of secondary endpoints will be assessed including investigator-reviewed DFS, metastasis-free survival, overall survival, safety/tolerability. Further, the authors will examine exploratory endpoints such as quality of life, pharmacokinetics, determination of the prevalence of genomic alterations and correlation with features of UC, genomic and proteomic assessment of tumor tissue and cell-free DNA samples from baseline and at recurrence to identify the predictive/prognostic value of biomarkers.

The authors initially plan to enroll 218 patients at 120 sites in 9 countries and began enrollment as of September 2021. Assuming a disease recurrence of 46%, the required sample size will be 70 centrally reviewed DFS events which will allow assessment of a hazard ratio of 0.5 with 80% power and a one-sided alpha of 0.025. The last patient is expected to complete treatment in 2024.