Infigratinib as Adjuvant Therapy for UC: Results From PROOF 302

In patients with muscle-invasive bladder cancer (MIBC) or upper tract urothelial carcinoma (UTUC), standard treatment consists of radical surgery with or without neoadjuvant cisplatin-based chemotherapy. However, recurrence rates following these treatments remains high, pointing to a need for more novel therapies.

As up to 70% of UTUC tumors contain FGFR3 alterations, targeting this pathway could result in better outcomes for patients. In the PROOF 302 trial, Petros Grivas, MD, PhD, and colleagues sought to determine the efficacy and safety of the selective FGFR1-3 inhibitor infigratinib against placebo in patients with high-risk invasive urothelial carcinoma (UC). The study’s results will be presented at the American Society of Clinical Oncology 2023 Annual Meeting.

The global, randomized, double-blind, placebo-controlled, phase 3 PROOF 302 trial enrolled patients with high-risk invasive UTUC or MIBC with FGFR3 alterations with residual (≥ypT2 and/or ypN+) tumor after neoadjuvant chemotherapy, or patients who were ineligible for or refused cisplatin-based adjuvant chemotherapy ≤120 days postsurgery.

Of the 617 patients screened, 188 (30.5%) had alterations in FGFR1-4 genes: 102/237 (43%) in UTUC, 85/369 (23%) in MIBC, and 1/11 (9%) with unknown tumor origin. The median patient age was 74 years (range, 32-90 years); 76% of patients were male, 55% of patients had UTUC, and 44% had MIBC. Patients were randomized 1:1 to receive either infigratinib 125 mg/day or placebo on days 1 through 21 every 28-day cycle for up to 52 weeks or until recurrence, unacceptable toxicity, or death.

The primary end point was centrally reviewed disease-free survival (DFS). The secondary end points were investigator-assessed DFS, metastasis-free survival, overall survival, and safety and tolerability. Exploratory end points included quality of life, pharmacokinetics, and genomic analysis of tumor and cell free DNA.

In UTUC, FGFR3 had 56% single-nucleotide variations (SNV) and insertions/deletions (INDELS), 40% amplifications, and 70% structural variants (SV). In MIBC, FGFR3 had 44% SNV and INDELS, 60% amplifications, and 30% SV.

FGFR alterations were only seen in 19% of all patients who were screened for PROOF-302, 71/237 (30%) of patients with UTUC and 48/369 (13%) of patients with MIBC. The trial was stopped early by the sponsor, but the genomic analysis conducted during the study provided insights into the prevalence of FGFR3 alteration.

An assessment of correlations between primary and secondary end points is ongoing. The nature and frequency of co-occurring alterations in tissue samples is also being investigated to help inform combination therapy options and resistance mechanisms.