A phase 1b clinical trial has revealed promising results for the combination of rogaratinib and atezolizumab in treating cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (UC) who have tumors overexpressing fibroblast growth factor receptor (FGFR) mRNA. The study, published in JAMA Oncology, highlights the potential of this combination therapy to offer a manageable and effective treatment option for a broader patient population, irrespective of PD-L1 expression or FGFR3 gene alterations.
The FORT-2 trial, a nonrandomized, open-label, multicenter study, enrolled 37 patients with untreated locally advanced or metastatic UC who were ineligible for cisplatin-based chemotherapy and had FGFR1/3 mRNA overexpression. Patients received either rogaratinib 600 mg or 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days. The primary objectives were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab.
Safety and Tolerability
The recommended phase 2 dose (RP2D) was established as rogaratinib 600 mg in combination with atezolizumab 1200 mg. The most common treatment-emergent adverse events (TEAEs) included diarrhea (62%), hyperphosphatemia (51%), and fatigue (41%). Grade 3 or higher TEAEs were reported in 73% of patients, with four grade 5 TEAEs reported, though none were related to the treatment. Rogaratinib-related grade 3 or higher TEAEs occurred less frequently in the 600 mg group (27%) compared to the 800 mg group (55%), indicating improved tolerability at the lower dose.
Efficacy Outcomes
At the RP2D, the overall response rate (ORR) was 53.8%, including 15% complete responses. Notably, 86% of responders did not have an FGFR3 gene alteration, and 79% had low PD-L1 expression. The median time to response was 2.1 months. Median progression-free survival was 6.1 months overall, with a 24-month progression-free survival rate of 27%. Median overall survival was 12.0 months, with a 24-month overall survival rate of 31%.
Clinical Implications
These findings suggest that combining FGFR inhibition with PD-L1 blockade may reverse immunosuppressive effects in the tumor microenvironment, sensitizing a broader population of UC patients to immune checkpoint blockade. According to the study, 48% of screened patients had FGFR mRNA overexpression, a significantly larger proportion than those with FGFR3 alterations. This suggests that selecting patients based on mRNA overexpression could extend the benefits of FGFR inhibitor therapy to a larger group.
Expert Commentary
"This study demonstrates that rogaratinib can be safely combined with atezolizumab to treat UC with FGFR1/3 overexpression," the researchers noted. "A favorable ORR of 53.8% was observed, which was not dependent on FGFR3 gene alteration or PD-L1 status, broadening the population of patients who may benefit."
While the study acknowledges limitations such as the small number of patients across biomarker-defined subsets and the exploratory nature of some biomarker analyses, the results offer a promising avenue for improving outcomes in cisplatin-ineligible urothelial cancer patients. Further research is warranted to validate these findings and optimize the integration of FGFR-targeted therapies in the evolving treatment landscape.
