| Resum: |
This nonrandomized clinical trial evaluates the safety, pharmacokinetics, and preliminary efficacy of rogaratinib in combination with the programmed cell death 1 ligand 1 inhibitor atezolizumab in cisplatin-ineligible patients with FGFR messenger RNA-positive, locally advanced/metastatic urothelial cancer. Can rogaratinib be safely combined with anti-programmed cell death 1 ligand 1 therapy to improve efficacy for patients with advanced/metastatic urothelial carcinoma harboring FGFR3 messenger RNA overexpression? In this phase 1b study of 153 patients with untreated locally advanced or metastatic urothelial cancer, the recommended dose of rogaratinib was 600 mg in combination with atezolizumab 1200 mg, which was tolerable and resulted in a high objective response rate despite low programmed cell death 1 ligand 1 expression among most patients. This study indicates that combination rogaratinib and atezolizumab is tolerable with relatively high efficacy and that selection of patients by FGFR3 messenger RNA overexpression may expand the fraction of patients who benefit from fibroblast growth factor receptor inhibitor therapy. The oral pan-fibroblast growth factor receptor inhibitor rogaratinib previously demonstrated encouraging safety and efficacy in a phase 1 study of patients with urothelial cancer (UC) overexpressing FGFR messenger RNA (mRNA). To evaluate the safety, pharmacokinetics, and preliminary efficacy of rogaratinib in combination with the programmed cell death 1 ligand 1 (PD-L1) inhibitor atezolizumab in cisplatin-ineligible patients with FGFR mRNA-positive, locally advanced/metastatic UC. The FORT-2 nonrandomized clinical trial was an open-label, single-arm, multicenter study conducted between May 15, 2018, and July 16, 2021, in 30 centers across Asia, Europe, and North America. Eligible patients had locally advanced/metastatic UC with FGFR1 / 3 mRNA overexpression and were ineligible for cisplatin-based chemotherapy. The data analysis was completed from July 2022 to September 2022. Patients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days. Primary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab. Among 153 patients screened, 73 (48%) had tumors with FGFR1/3 mRNA overexpression, and 37 patients were enrolled and treated (median [range] age, 75. 0 [47. 0-85. 0] years; 32 [87%] male). The most common treatment-emergent adverse events (TEAEs) included diarrhea in 23 patients (62%), hyperphosphatemia in 19 (51%), and fatigue in 15 (41%). Grade 3 or higher TEAEs were reported in 27 patients (73%), and 4 grade 5 TEAEs were reported, though unrelated to treatment. The RP2D was rogaratinib 600 mg in combination with atezolizumab 1200 mg. At the RP2D, the overall response rate was 53. 8% in the rogaratinib 600 mg group, including 4 patients (15%) with complete responses; 12 responders (86%) did not have an FGFR3 gene alteration, and 11 (79%) had low PD-L1 expression. In this phase 1b nonrandomized clinical trial, rogaratinib plus atezolizumab demonstrated a manageable safety profile, with no unexpected safety signals. Efficacy for this combination at the RP2D was observed in tumors with low PD-L1 and was not dependent on FGFR3 gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and FGFR mRNA overexpression. ClinicalTrials. gov Identifier:. |
visitant ::
identificació
(Hospital Ramón y Cajal (Madrid))
