Targeting FGFR3 Alterations with Adjuvant Infigratinib in Invasive Urothelial Carcinoma: the Phase III PROOF 302 Trial

Abstract

PROOF 302 is an ongoing randomized, double-blind, placebo-controlled, adjuvant phase III trial (NCT04197986) in approximately 218 patients from 120 centers worldwide. Eligibility criteria include post-surgical high-risk muscle-invasive upper tract urothelial cancer (85% of patients) or urothelial bladder cancer (15%), susceptible FGFR3 alterations (activating mutations, gene fusions or rearrangements), ≤120 days following radical surgery and ineligible for/or refusing cisplatin-based (neo)adjuvant chemotherapy. Patients receive either oral infigratinib 125 mg or placebo daily on days 1–21 of a 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity or death. Primary end point: centrally determined disease-free survival (DFS); secondary end points: investigator-assessed DFS, metastasis-free survival, overall survival and safety/tolerability; exploratory end points: correlative biomarker analysis, quality-of-life and infigratinib pharmacokinetics.

Safety and efficacy of the pan-FGFR inhibitor erdafitinib in advanced urothelial carcinoma and other solid tumors: A systematic review and meta-analysis

“…In efficacy analysis, erdafitinib can increase the PFS significantly, among which, patients with FGFR mutations have a better response than those with fusions, while in FGFR gene fusion, FGFR3-TACC3 is the most sensitive gene alteration. Further studies on single-use and combined therapy of erdafitinib are ongoing, such as the phase III PROOF 302 trial ( ), which evaluates the efficacy of the FGFR1–3 inhibitor infigratinib in invasive urothelial carcinoma, which provides evidence for FGFR inhibitors in clinical decisions ( 48 ). After more clinical trials are published, the discoveries will be further improved.…”

Recent advances in cancer-associated fibroblast: Biomarkers, signaling pathways, and therapeutic opportunities

“…Therapies against other cytokines and signaling pathways in CAFs are explored in different cancers. [100][101][102][103][104][105][106][107] In gratinib [104,105] (BGJ398) is a broblast growth factor receptor 1-3 inhibitor that has shown promising results in advanced and metastatic cholangiocarcinoma with FGFR2 gene fusions or rearrangements. BL-8040 [106] is a CXCR4 antagonist and, when combined with PD-1 blockade, may expand the bene t of chemotherapy in PDAC.…”

Understanding Adjuvant Therapy for Upper Tract Urothelial Carcinoma

“…Unfortunately, the PROOF 302 trial which attempted to explore adjuvant treatment with a small molecule fibroblast growth factor receptor (FGFR) inhibitor in patients with urothelial cancers harboring FGFR3 mutations, mutations which are enriched in UTUC versus urothelial cancer of the bladder, recently closed early because of poor accrual. 22,23 Biomarkers to define who needs adjuvant therapy and biomarkers to define who benefits from specific adjuvant approaches are ultimately required to usher in the era of precision perioperative therapy for UTUC.…”