ASCO 2023: FGFR3 Alterations in PROOF 302: A Phase III Trial of Infigratinib (BGJ398) as Adjuvant Therapy in Patients with Invasive Urothelial Carcinoma

( The 2023 ASCO annual meeting included a bladder cancer session, featuring a presentation by Dr. Petros Grivas discussing FGFR3 alterations in PROOF 302, a phase III trial of infigratinib (BGJ398) as adjuvant therapy in patients with invasive urothelial carcinoma. Radical surgery with or without neoadjuvant cisplatin-based chemotherapy is standard of care in fit patients with muscle invasive urothelial carcinoma of the bladder or upper tract urothelial carcinoma. However, recurrence rates are high, underscoring the need for novel therapies. Since up to 70% of upper tract urothelial carcinoma and 20% of urothelial carcinoma of the bladder tumors are reported to harbor FGFR3 alterations, targeting this pathway is a rational approach aiming to reduce recurrence risk and improve outcomes for these patients after surgery. Infigratinib is a selective FGFR1–3 inhibitor with efficacy in advanced urothelial carcinoma with FGFR3 alterations.1 PROOF 302 investigated the efficacy and safety of adjuvant infigratinib vs placebo in patients with high-risk invasive urothelial carcinoma, with Dr. Grivas and colleagues presenting FGFR3 alteration data at ASCO 2023.

PROOF 302 is a global, randomized, double-blind, placebo-controlled, phase III trial for patients with high-risk invasive upper tract urothelial carcinoma or urothelial carcinoma of the bladder (≤15%) with FGFR3 alteration (i.e. mutation, gene fusion/translocation) with residual (≥ypT2 and/or ypN+) tumor after neoadjuvant chemotherapy, or patients ineligible for, or refusing, cisplatin-based adjuvant chemotherapy, ≤120 days post-surgery. Patients were randomized 1:1 to infigratinib 125 mg or placebo daily on days 1–21 every 28 days for up to 52 weeks or until recurrence, unacceptable toxicity, or death. The trial design for PROOF 302 is as follows:

PROOF 302.jpg

The primary endpoint was centrally reviewed disease-free survival (DFS). Secondary endpoints included investigator-assessed DFS, metastasis-free survival, overall survival, safety/tolerability. Exploratory endpoints included quality of life metrics, pharmacokinetics, genomic analysis of tumor, and cfDNA.

A relevant question is the prevalence of FGFR3 alterations in the primary tissue of MIBC. Dr. Grivas and colleagues presented results of the genomic analysis of radical surgery tissues from patients screened for the trial using the FoundationOne platform. Out of 617 patients screened, 188 (30%) had alterations in FGFR 1-4 genes: 43% in upper tract urothelial carcinoma, 23% in MIBC, and 9% with unknown tumor origin. Of these 188 patients, there were 193 single nucleotide variants and short insertions/deletions, 29 amplifications, 1 deletion, and 20 structural variants (fusions and other genomic rearrangements). The median age 74 (range: 32-90 years), 76% were male, 55% had upper tract urothelial carcinoma, and 44% had urothelial carcinoma of the bladder. FGFR3 alterations were noted in 119 out of 617 patients screened for PROOF-302 (19%): 30% of upper tract urothelial carcinoma, 13% of bladder urothelial carcinoma, and 9% of unknown tumor site. As follows is a figure highlighting the frequency of FGFR3 alterations in different age groups:

PROOF 302.jpg

The oncoplot for FGFR1-4 gene alterations is as follows:

ASCO PROOF 302.jpg

Dr. Grivas concluded his presentation discussing FGFR3 alterations in PROOF 302 with the following take-home points:

  • FGFR3 alterations were seen in only 19% of all patients screened for PROOF-302, a trial that was enriched for upper tract urothelial carcinoma: 30% of upper tract urothelial carcinoma and 13% of urothelial carcinoma of the bladder
  • The trial was stopped early by the sponsor, but the genomic analysis provides insights into the prevalence of FGFR3 alterations. Assessment of correlations with the primary/secondary endpoints is ongoing
  • The nature and frequency of co-occurring alterations in tissue samples is being investigated to help inform combination therapy strategies and putative resistance mechanisms

Presented by: Petros Grivas, MD, PhD, Division of Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023. 


  1. Pal SK, Rosenberg JE, Hoffman-Censits JH, et al. Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations. Cancer Discov. 2018 Jul;8(7):812-821.