Rogaratinib May Be Effective for Patients With Bladder Cancer and FGFR3 DNA Alterations


Rogaratinib did not display a significant benefit over chemotherapy in patients with FGFR mutated bladder cancer, but the targeted treatment did generate encouraging responses among those with FGFR3 DNA alterations.

Cora N. Sternberg, MD

Cora N. Sternberg, MD

For patients with urothelial cancer and FGFR3 alterations, targeted treatment with rogaratinib (BAY1163877) may deliver preferred responses compared with chemotherapy, according to a subgroup analysis of patients enrolled in the phase 2/3 FORT-1 trial (NCT03410693), although results with the larger study populations were not promising.

Findings from FORT-1, which were published in the Journal of Clinical Oncology, demonstrated that the overall response rate (ORR) for patients with FGFR DNA alterations was 52.4% (95% CI, 29.8%-74.3%) with rogaratinib (n = 21) and 26.7% (95% CI, 7.8%-55.1%) with chemotherapy (n = 15). However, in the larger study population, the ORR was 20.7% (95% CI, 12.7%-30.7%) with rogaratinib and 19.3% (95% CI, 11.7%-29.1%) with chemotherapy. According to investigators, the exploratory analysis suggests that FGFR3 alterations in association with FGFR1/3 mRNA overexpression may be a better precentor of rogaratinib response.

“Rogaratinib demonstrated efficacy comparable with standard chemotherapy and a manageable safety profile,” wrote Cora N. Sternberg, MD, of Weill Cornell Medicine, and co-investigators. “Prespecified efficacy criteria were not met for continuation to phase III in this population. An exploratory analysis suggested that rogaratinib may have greater antitumor benefit in patients with both FGFR3 mRNA overexpression and an FGFR DNA alteration, which warrants further investigation.”

Many patients with locally advanced or metastatic urothelial carcinoma experience recurrence following platinum-based chemotherapy and consequently face poor prognoses. Current second-line treatments include immunotherapies and anti-body conjugates—3 immune checkpoint inhibitors are approved in this setting. However, immunotherapy does not benefit all patients and metastatic urothelial cancer poses a serious threat to patients who relapse or progress following frontline treatment.

FGFR signaling has gained attraction across various cancer subtypes—but is increasingly being recognized as a key signaling pathway in late-stage muscle invasive urothelial carcinoma. FGFR signaling affects tumorigenesis, and among the 4 subtypes, FGFR3 mutations have been shown to be particularly prominent in urothelial cancers; as many as 42% of urothelial cancer cases have FGFR3 mutations, including 20% of metastatic cases and 15% of muscle-invasive bladder tumors.

Moreover, research has suggested that 42% of bladder tumors that do not have a FGFR3 DNA mutation do have FGFR3 protein overexpression—indicating that patients with wild-type or FGFR3-mutated tumors could potentially benefit from FGFR-targeted therapies.

The FDA has approved erdafitinib (Balversa) for patients with FGFR3 or FGFR2 alterations in this setting. Like rogaratinib, erdafitinib is a pan-fibroblast growth factor receptor inhibitor. A phase 2 study (NCT02365597) showed that erdafitinib yielded a 40% ORR in this setting, as well as a median progression-free survival (PFS) of 5.5 months and overall survival (OS) of 13.8 months.

Similarly, in a phase 1 study (NCT01976741), rogaratinib demonstrated promising safety and efficacy in treating patients with advanced cancers and with FGFR1-3 mRNA overexpression and/or FGFR3-activating mutations. Specifically, the ORR was 24% in a subset of patients with advanced muscle-invasive urothelial carcinoma.

The FORT-1 trial was a randomized, open-label trial which therefore enrolled patients with locally advanced or metastatic urothelial carcinoma who had already undergone at least 1 line of treatment with a platinum-containing regimen. Patients were randomly assigned to receive either rogaratinib at a dose of 800-mg orally twice daily in a 3-week cycles or chemotherapy every 3 weeks (either docetaxel at 75 mg/m2, paclitaxel at 175 mg/m2, or vinflunine at 320 mg/m2).

Between May 31, 2018, and March 8, 2019, investigators conducted biomarker screening for 683 patients. They identified FGFR1/3 mRNA overexpression in 664 (97.2%) of patients. Among this group, 456 (68.7%) had FGFR overexpression at initial testing.

Ultimately, 175 patients met the screening eligibility criteria for the trial and 87 were randomly assigned to receive rogaratinib and 88 were assigned to chemotherapy. In the chemotherapy treatment arm, 48.8% of patients received vinflunine (n = 40), 29.3% received paclitaxel (n = 24), and 22.0% received docetaxel (n = 18). Of note, 7.4% of patients had wild-type PIK3CA/RAS, 10.9% had PIK3CA and/or RAS mutations, and 17.7% had an unknown mutation status.

The median data cutoff was 10.8 months (95% CI, 10.1-11.7), at which point the median treatment duration was 12.0 weeks with rogaratinib (range, 2.1-40.7) and weeks with 9.4 weeks with chemotherapy (range, 0.1-39.1 weeks), this translated to approximately 4 treatment cycles in both treatment groups.

Approximately 43.0% (n = 37) experienced grade 3 treatment-emergent adverse events (TEAEs) in the rogaratinib arm. In the chemotherapy arm, 39.0% (n = 32) of patients experienced grade 3 TEAEs. The percentage of patients who experienced grade 4 TEAEs in the 2 arms was 4.7% (n = 4) and 18.3% (n = 15), respectively.

Retinal disorders emerged with rogaratinib; 6 patients (7.0%) experienced grade 2 or worse retinal disorders while no patients in the chemotherapy arm experienced this toxicity. Moreover, 26 patients receiving rogaratinib (30.2%) and 3 patients receiving chemotherapy (3.7%) experienced any-grade retinal disorders.

In addition, 19 patients in the study developed a grade 5 TEAE, including 14 patients receiving targeted treatment (16.3%) and 5 receiving chemotherapy (6.1%). The most common grade 5 events included generally physical health deterioration (n = 3) and dyspnea (n = 3). None of these events were determined to be drug related. One patient receiving chemotherapy developed a grade 5 respiratory tract infection which was considered to be drug related.

Notably, the rate of TEAEs was determined to be similar for both patients who received rogaratinib at a dose of 800 mg twice daily and for patients who required the reduced dose of 600 mg twice daily.

“These ORR and OS results should be interpreted with caution because of the small sample size and retrospective exploratory nature,” remarked study authors. “Overall, the improved ORR with rogaratinib seen in this study in FGFR mRNA-positive patients with FGFR genetic DNA alterations is of interest and may warrant further evaluation.”


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 [published online ahead of print, 2022 Oct 14]. J Clin Oncol. 2022;JCO2102303. doi:10.1200/JCO.21.02303

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