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Clinical Trial
. 2024 Nov;10(11):1565-1570.
doi: 10.1001/jamaoncol.2024.3900. Epub 2024 Sep 19.

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

Randy F Sweis  1 , Pablo Gajate  2 , Rafael Morales-Barrera  3 , Jae-Lyun Lee  4 , Andrea Necchi  5   6 , Filippo de Braud  5 , Nicolas Penel  7 , Viktor Grünwald  8 , Marco Maruzzo  9 , Johannes Meran  10 , Tatiane Cristine Ishida  11 , Weichao Bao  11 , Yinghui Zhou  12 , Peter Ellinghaus  13   14 , Jonathan E Rosenberg  15
Affiliations
Clinical Trial

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

Randy F Sweis et al. JAMA Oncol. 2024 Nov.

Abstract

Importance: 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).

Objective: 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.

Design setting and participants: 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.

Interventions: Patients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days.

Main outcomes and measures: Primary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab.

Results: 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.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT03473756.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Sweis reported grants paid to institution from Ascendis, AstraZeneca, Astellas, ALX Oncology, Bayer, BMS, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Loxo Oncology, Lilly, Merck, Moderna, Mirati, Novartis, Pfizer, Pionyr, Pyxis, QED, Regeneron, and Scholar Rock outside the submitted work; personal fees from AbbVie, Aveo, Eisai, Exelixis, Gilead, Janssen, and Lilly outside the submitted work; and a patent pending for Neoantigens in Cancer (PCT/US2020/031357). Dr Gajate reported personal fees from BMS, Merck, Roche, Pfizer, Astellas, Janssen, and MSD outside the submitted work. Dr Morales-Barrera reported serving in an advisory role for MSD, Pfizer, Merck, Janssen, and Astellas, as well as receiving honoraria or travel expenses from Roche, Sanofi Aventis, Astellas, Janssen, MSD, Bayer, Merck, and Pfizer. Dr de Braud reported personal fees from Pierre Fabre, Mattioli 1885, MSD, IQVIA, BMS, Indena, Incyte, Taiho, Menarini, Novartis, Roche, Sanofi, AccMed, Itanet, ESO, Dephaforum, Nadirex, Events, Fare Comunicazione, Motore Sanità, Effetti, Ambrosetti, Dynamicom Education, and AstraZeneca outside the submitted work. Dr Grünwald reported personal fees from Bristol Myers Squibb, Merck Serono, MSD, AstraZeneca, and Astellas during the conduct of the study; personal fees from AstraZeneca, Gilead, Pfizer, Novartis/AAA, Janssen-Cilag, Amgen, Ipsen, Eisai, Debiopharm, Apogepha, PCI Biotech, Synthekine, and Oncorena outside the submitted work. Dr Rosenberg reported personal fees from Bayer during the conduct of the study; personal fees from Janssen, AstraZeneca, Chugai, Merck, Seagen, Pfizer, Astellas, Genentech/Roche, EMD-Serono, Boehringer Ingelheim, Lilly/Loxo Oncology, Tyra Biosciences, QED Therapeutics, Gilead, Hengrui, Century Therapeutics, and Aktis Consultant outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Disposition
MTD indicates maximum tolerated dose; RP2D, recommended phase 2 dose. aPrescreen failure was defined as patients who provided signed consent for FGFR testing but, for any reason, did not sign the consent form for study treatment eligibility. bScreen failure was defined as patients who provided signed consent for study treatment eligibility but, for any reason, terminated the study before the start of study treatment or did not meet the inclusion or exclusion criteria. cAll patients assigned to study treatment received at least 1 dose of study treatment.
Figure 2.
Figure 2.. Response, Duration of Treatment, Follow-Up, and Percentage Change in Tumor Size by FGFR3, Programmed Cell Death 1 Ligand 1 (PD-L1), and Resistance Alteration (PI3K and RAS) Expression Status
Data are presented for all treated patients (A) and for patients who received rogaratinib 600 mg twice daily (B; the dashed lines indicate thresholds for partial response and progressive disease, according to Response Evaluation Criteria in Solid Tumors, version 1.1). In relation to percentage change in tumor size, no FGFR3 fusions were detected. Three patients did not have complete values for tumor size at all postbaseline assessments and were excluded from the analysis. One patient achieved a 48% reduction in target lesion, corresponding to a partial response, but reported progressive disease in nontarget lesions on first scan; therefore, best overall response was determined as progressive disease. a2.1 (95% CI, 2.0-2.1) months.
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