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

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.

Clinical trial identification

NCT01703481; Release date: March 22, 2012

Legal entity responsible for the study

Janssen Research & Development, LLC

Funding

Janssen Research & Development, LLC

Disclosure

J-C. Soria: Honoraria: Johnson and Johnson. A. Cervantes: Research funding: Janssen. J. Tabernero: Consultant/Advisory: Amgen, Boehringer Ingelheim, Celgene, Chugai, Imclone, Lilly, Merck, Merck Serono, Millennium, Novartis, Roche, Sanofi, Symphogen and Taiho. P.N. Lara: Research funding: Johnson & Johnson. A. Spira: Consultant/Advisory: Novartis, Clovis, Roche, Astellas, Ariad Honoraria: Roche, Ariad, Clovis Research funding: Janssen . B. Zhong, A. Ademi Santiago-Walker, J. Bussolari, F.R. Luo, H. Xie: Employee of Janssen Research & Development and Johnson & Johnson stock holder. P. Hammerman: Consultant/Advisory: Janssen Honoraria: Janssen. All other authors have declared no conflicts of interest.