Safety and activity of the pan–fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients with advanced urothelial carcinoma

Abstract

Background: Erdafitinib (JNJ‐42756493) is a potent, oral pan‐FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first‐in‐human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from patients with urothelial carcinoma (UC) from this study. Methods: This 4‐part study enrolled patients age > 18 years with advanced solid tumors. Dose escalation (Part 1) followed a 3 + 3 design, with patients receiving ascending doses of erdafitinib either once daily (QD) or intermittently (7 days on/7 days off ). Subsequent parts of the study (Part 2, pharmacodynamics cohort; Parts 3 and 4, dose‐expansion cohorts for recommended phase 2 doses of 9 mg QD and 10 mg intermittently, respectively) required documented FGFR‐biomarker positive disease (including activating mutations and translocations; or other FGFR‐activating aberrations, Parts 2 and 3). Results: Twenty‐eight patients with UC were treated at 2 mg QD (n = 1), 9 mg QD (n = 12), 10 mg intermittent (n = 13), 12 mg QD (n = 1), or 12 mg intermittent (n = 1). Across these dose levels, median treatment duration was 3.3 mo. The most common drug‐related AEs were hyperphosphatemia (57%), dry mouth (50%), diarrhea (46%), and dry skin (46%); all of these were grade 1 or 2 severity, except for 1 case of grade 3 hyperphosphatemia (4%) and 2 cases of grade 3 diarrhea (7%). The most common grade >3 AEs were anemia (18%), hand‐foot syndrome (14%), and stomatitis (11%). Among FGFR‐positive, response evaluable patients (as of 22 Apr 2016), the objective response rate (Complete Response + Partial Response [PR]) was 43.5% (10/23; 95% CI 23.2%, 65.5%); 17.4% (4/23) had stable disease. 6/11(54.5%) patients treated at 9 mg QD and 4/11(36.4%) patients treated 10 mg intermittent achieved PR. With a median follow‐up of 3.8 mo, median duration of response was 7.2 mo (95% CI 3.3, 15.3) and progression‐free survival was 5.1 mo (95% CI 2.8, 5.9). Conclusions: Erdafitinib produces encouraging clinical activity and tolerability in patients with FGFR‐positive UC, warranting further study.