FDA Grants Erdafitinib Breakthrough Designation for Urothelial Carcinoma

Peter F. Lebowitz, MD, PhD

The FDA has granted a breakthrough therapy designation to erdafitinib for the treatment of metastatic urothelial carcinoma, according to Janssen, the manufacturer of the oral pan-FGFR tyrosine kinase inhibitor.

The designation, which will expedite the review and development of erdafitinib, is based on the phase II study BLC2001 in which the TKI induced a 42% overall response rate (ORR) in 59 patients with FGFR-positive relapsed/refractory metastatic urothelial carcinoma.

“For patients diagnosed with urothelial cancer, outcomes are unfortunately disheartening due to the aggressiveness of the disease,” Peter Lebowitz, MD, PhD, global therapeutic area head, oncology, Janssen Research & Development, said in a press release. "Through the continued development of erdafitinib, and working closely with the FDA, we look forward to bringing a potential new treatment option to patients.”

The global BLC2001 trial evaluated ORR in patients with pretreated metastatic or unresectable FGFR alteration—positive urothelial carcinoma who received 1 of 3 doses of erdafitinib. Across all regimens, the ORR was 35% and the confirmed disease control rate (DCR) was 76%. Median progression-free survival (PFS) across all dosing cohorts was 5.1 months.

The highest rate of response occurred with continuous dosing of erdafitinib at 8 mg/day, with uptitration to 9 mg/day allowed. In this group (n = 59), the ORR was 42%, with a complete response in 5% of patients and a partial response in 37%. The DCR in this group was 81%, and the median duration of response was 5.4 months, with many responses ongoing at the time of the analysis. Fifty-seven percent of patients who received 8 mg/day continuous dosing were still alive at 1 year.

Investigators found that 75% of patients treated with 8 mg of continuous erdafitinib saw a reduction in the sum of target lesion diameters, regardless of the kind of gene alterations.

Overall, FGFR alterations have been found in approximately 20% to 30% of patients with urothelial carcinoma, with amplifications, mutations, and fusions in FGFR most commonly observed in the luminal cluster I subtype of urothelial carcinoma.

Patients were randomly assigned to oral erdafitinib at 6 mg/day continuous dosing or 10 mg/day intermittent (7 days on/7 days off dosing) for 28-day cycles. Investigators later opened a third cohort evaluating 8 mg/day of continuous dosing following an interim analysis.

All patients in the trial had FGFR2/FGFR3 mutations or fusions and had progressed during or following at least 1 line of prior systemic chemotherapy or within 12 months of receiving neoadjuvant or adjuvant chemotherapy.

At an interim analysis, enrollment in the intermittent dosing group was stopped after 33 patients were treated. Enrollment continued for the 6 mg/day continuous dosing regimen (n = 78). Based on pharmacokinetic and pharmacodynamics modeling and the clinical safety of 6 mg/day, investigators decided to proceed with an 8-mg/day continuous dosing regimen. This arm is ongoing until 100 patients have been enrolled.

Patients in the 8 mg/day arm could be further uptitrated to 9 mg/day if they had not reached a target serum phosphate level ≥5.5 mg/dL by day 14 and if they had no treatment-related adverse events (TRAEs). Data from the first 59 patients enrolled in this arm were presented.

The median age of patients was 67 in the 8 mg/day group, and 93% of patients had an ECOG performance status of 0 or 1. Overall, 46% of patients had received 1 prior therapy and 31% were treated with 2 prior regimens, which included immunotherapy for 19% of patients. Seventy-six percent of patients had visceral metastases, and the creatinine clearance rate was 40 to 59 mL/min for 54% of patients.

The ORR was 35% and 24% in the continuous 6 mg/day group and the 10 mg/day intermittent group, respectively, with DCRs of 73% in each group. The median PFS was 5.1 for the continuous 6 mg/day dose and 4.0 months for the intermittent 10 mg/day dose. The 1-year overall survival (OS) rates were 32% and 31%, for the continuous and intermittent groups, respectively.

In the safety analysis, erdafitinib was well tolerated with no treatment-related deaths. Ten percent discontinued treatment due to TRAEs. In 96 patients treated with the 8 mg/day continuous dose, the most common TRAEs of any grade were hyperphosphatemia (69%), stomatitis (47%), diarrhea (42%), dry mouth (42%), and dysgeusia (33%). The most common grade ≥3 TRAEs were stomatitis (8%), asthenia (3%), and diarrhea (3%).

A phase III study (NCT03390504) is comparing erdafitinib at 8 mg/day with vinflunine (Javlor), docetaxel, or pembrolizumab (Keytruda) for patients with advanced urothelial carcinoma with selected FGFR gene alterations. The open-label trial has an estimated enrollment of 630 participants, with a planned primary completion date of November 2020. The primary endpoint is OS.

Loriot Y, Necchi A, Park SH, et al. Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): Phase 2 continuous versus intermittent dosing. 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, Calif. Abstract 411.