Rogaratinib Is Noninferior to Chemo in Pretreated FGFR1/3 mRNA+ Locally Advanced or Metastatic Urothelial Carcinoma

Rogaratinib induced an objective response rate similar to that of chemotherapy in patients with FGFR1/3 mRNA–positive locally advanced or metastatic urothelial carcinoma who have received at least 1 prior platinum-containing chemotherapy.

Rogaratinib, an oral FGFR1-4 inhibitor, induced an objective response rate (ORR) similar to that of chemotherapy in patients with FGFR1/3 mRNA–positive locally advanced or metastatic urothelial carcinoma who have received at least 1 prior platinum-containing chemotherapy, according to data from the phase 2/3 FORT-1 trial (NCT03410693) published in the Journal of Clinical Oncology.

The primary end point for the trial was overall survival (OS), with ORR analysis planned following phase 2 accrual. Investigators completed a full interim analysis of phase 2 data, but stopped enrollment before progression to phase 3 because of comparable efficacy between treatments.

The median OS was 8.3 months (95% CI, 6.5–not estimable [NE]) in the experimental arm and 9.8 months (95% CI, 6.8-NE) with chemotherapy (HR, 1.11; 95% CI, 0.71-1.72; P = .67)

Patients assigned to rogaratinib had an ORR of 20.7% (95% CI, 12.7%-30.7%) compared with 19.3% (95% CI, 11.7%-29.1%) for chemotherapy (P = .48). Two patients (2.3%) in the experimental arm and 3 (3.4%) in the chemotherapy arm achieved a complete response. Sixteen (18.4%) and 14 (15.9%), respectively, had a partial response.

Investigators wrote that these appear to be the first data demonstrating comparable efficacy and manageable safetybetween FGFR-directed therapy and chemotherapy in patients with FGFR-altered urothelial carcinoma.

Recurrence is high and prognosis is poor following first-line platinum-based chemotherapy for patients with locally advanced or metastatic urothelial carcinoma. Current second-line treatments include immunotherapy and antibody-drug conjugates. However, many patients do not benefit from immunotherapy, and metastatic urothelial carcinoma remains deadly for patients who relapse or progress during first-line chemotherapy.

In previous results from a phase 1 trial (NCT01976741), rogaratinib showed promising efficacy in patients with FGFR1/3 mRNA–positive urothelial carcinoma. Investigators conducted this trial to evaluate the safety and efficacy of rogaratinib vs chemotherapy following at least 1 platinum-containing regimen in this patient population.

The FORT-1 trial enrolled adults with locally advanced or metastatic, histologically or cytologically confirmed urothelial carcinoma, including urinary bladder, renal pelvis, ureters, and urethra. Patients needed to have an ECOG performance status of 0 or 1 and archival or fresh tumor biopsy available. Only those with FGFR1/3 mRNA–positive tumors were eligible.

From May 31, 2018, to March 8, 2019, investigators on the FORT-1 trial at 161 sites in Asia, Europe, North America, and Australia identified 456 patients who had FGFR1/3 mRNA overexpression at initial testing, 175 of whom met eligibility criteria. Eighty-seven patients were then randomly assigned to of 800 mg of oral rogaratinib twice daily in 3-week cycles. Eighty-eight were assigned to chemotherapy with 75 mg/m2 docetaxel (22.0%), 175 mg/m2 paclitaxel (29.3%), or 320 mg/m2 vinflunine (48.8%) in 3-week cycles.

Secondary end points included progression-free survival, ORR, disease control rate (DCR), duration of response, safety, and tolerability.

The median patient age was 69.0 years (range, 36-89), and 67.4% came from North America, Western Europe, Israel, or Australia. ECOG performance status was 1 in 57.7% of patients, and the bladder was the most common site of primary tumor (57.7%). One-third of patients had liver metastases.

At a median follow-up of 10.8 months (95% CI, 10.1-11.7), the median treatment duration was 12.0 weeks (range, 2.1-40.7) with rogaratinib and 9.4 weeks (range, 0.1-39.1) with chemotherapy. Patients in both groups received a median of 4 treatment cycles (range, 1-14).

At the analysis cutoff date, 6 patients (6.9%) were ongoing with rogaratinib and 4 (4.5%) were ongoing with chemotherapy. Disease progression, including radiologic progression, was the most common primary reason for treatment discontinuation in 53 patients (60.9%) receiving rogaratinib and 47 (53.4%) receiving chemotherapy. Zero patients in the experimental arm discontinued for clinical progression compared with 6 (6.8%) with chemotherapy.

The median DOR was 4.9 months (95% CI, 3.5-9.1) with rogaratinib and 5.8 months (95% CI, 3.5-7.7) with chemotherapy. Investigators observed no differences in ORR or DCR were in patients with confirmed PIK3CA and RAS mutations.

Thirty-seven patients (47.7%) in the rogaratinib arm experienced grade 3/4 treatment-emergent adverse effects (TEAEs) compared with 32 (57.3%) in the chemotherapy arm. Of note, investigators observed no grade 3 neutropenia and just 1 incident of grade 4 neutropenia in the experimental arm compared with 13 incidents (15.9%) of grade 3 and 7 incidents (8.5%) of grade 4 neutropenia in the chemotherapy arm.

Fourteen patients (16.3%) in the rogaratinib arm and 5 (6.1%) in the chemotherapy arm experienced fatal TEAEs. The most common grade 5 events with rogaratinib were general physical health deterioration (n = 3) and dyspnea (n = 3). None of the events in the experimental arm were considered drug-related, compared with 1 incident of respiratory tract infection in the chemotherapy arm deemed to be related to treatment. Of patients with grade 5 TEAEs, 78.6% who received rogaratinib and 80.0% who received chemotherapy had stage IVB disease at baseline.


Sternberg CN, Petrylak DP, Bellmunt J, et al. FORT-1: phase II/III study of rogaratinib versus chemotherapy in patients with locally advanced or metastatic urothelial carcinoma selected based on FGFR1/3 mRNA expression. J Clin Oncol. Published online October 14, 2022. doi:10.1200/JCO.21.02303