Reference Detail

Ref Type

Journal Article

PMID

(39298147)

Authors

Sweis RF, Gajate P, Morales-Barrera R, Lee JL, Necchi A, de Braud F, Penel N, Grünwald V, Maruzzo M, Meran J, Ishida TC, Bao W, Zhou Y, Ellinghaus P, Rosenberg JE

Title

Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer: The FORT-2 Phase 1b Nonrandomized Clinical Trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JAMA oncology			2024 Sep 19		JAMA Oncol

URL

Abstract Text

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: NCT03473756.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR3 over exp	transitional cell carcinoma	sensitive	Atezolizumab + Rogaratinib	Phase I	Actionable	In a Phase Ib trial (FORT-2), Tecentriq (atezolizumab) and Rogaratinib (BAY 1163877) combined therapy demonstrated safety and led to an objective response rate (ORR) of 43% (16/37, 5 complete and 11 partial responses), disease control rate of 65% (24/37), median progression-free survival of 6.1 mo, median overall survival of 12.0 mo, and ORR of 54% (14/26) at the RP2D of 600mg in cisplatin-ineligible patients with metastatic urothelial cancer with FGFR1 or FGFR3 overexpression (PMID: 39298147; NCT03473756).	39298147