Randy F. Sweis, Pablo Gajate, Rafael Morales-Barrera, Jae-Lyun Lee, Andrea Necchi, Filippo de Braud, Nicolas Penel, Viktor Grünwald, Marco Maruzzo, Johannes Meran, Tatiane Cristine Ishida, Weichao Bao, Yinghui Zhou, Peter Ellinghaus, Jonathan E. Rosenberg
{"title":"罗格替尼联合阿特珠单抗治疗不符合顺铂治疗条件的表皮生长因子受体RNA过表达尿路上皮癌患者","authors":"Randy F. Sweis, Pablo Gajate, Rafael Morales-Barrera, Jae-Lyun Lee, Andrea Necchi, Filippo de Braud, Nicolas Penel, Viktor Grünwald, Marco Maruzzo, Johannes Meran, Tatiane Cristine Ishida, Weichao Bao, Yinghui Zhou, Peter Ellinghaus, Jonathan E. Rosenberg","doi":"10.1001/jamaoncol.2024.3900","DOIUrl":null,"url":null,"abstract":"ImportanceThe 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 <jats:italic>FGFR</jats:italic> messenger RNA (mRNA).ObjectiveTo 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 <jats:italic>FGFR</jats:italic> mRNA-positive, locally advanced/metastatic UC.Design, Setting, and ParticipantsThe 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 <jats:italic>FGFR1</jats:italic>/<jats:italic>3</jats:italic> mRNA overexpression and were ineligible for cisplatin-based chemotherapy. The data analysis was completed from July 2022 to September 2022.InterventionsPatients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days.Main Outcomes and MeasuresPrimary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab.ResultsAmong 153 patients screened, 73 (48%) had tumors with <jats:italic>FGFR1/3</jats:italic> 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 <jats:italic>FGFR3</jats:italic> gene alteration, and 11 (79%) had low PD-L1 expression.Conclusions and RelevanceIn 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 <jats:italic>FGFR3</jats:italic> gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and <jats:italic>FGFR</jats:italic> mRNA overexpression.Trial RegistrationClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://clinicaltrials.gov/study/NCT03473756\">NCT03473756</jats:ext-link>","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":null,"pages":null},"PeriodicalIF":22.5000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer\",\"authors\":\"Randy F. Sweis, Pablo Gajate, Rafael Morales-Barrera, Jae-Lyun Lee, Andrea Necchi, Filippo de Braud, Nicolas Penel, Viktor Grünwald, Marco Maruzzo, Johannes Meran, Tatiane Cristine Ishida, Weichao Bao, Yinghui Zhou, Peter Ellinghaus, Jonathan E. Rosenberg\",\"doi\":\"10.1001/jamaoncol.2024.3900\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"ImportanceThe 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 <jats:italic>FGFR</jats:italic> messenger RNA (mRNA).ObjectiveTo 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 <jats:italic>FGFR</jats:italic> mRNA-positive, locally advanced/metastatic UC.Design, Setting, and ParticipantsThe 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 <jats:italic>FGFR1</jats:italic>/<jats:italic>3</jats:italic> mRNA overexpression and were ineligible for cisplatin-based chemotherapy. The data analysis was completed from July 2022 to September 2022.InterventionsPatients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days.Main Outcomes and MeasuresPrimary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab.ResultsAmong 153 patients screened, 73 (48%) had tumors with <jats:italic>FGFR1/3</jats:italic> 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 <jats:italic>FGFR3</jats:italic> gene alteration, and 11 (79%) had low PD-L1 expression.Conclusions and RelevanceIn 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 <jats:italic>FGFR3</jats:italic> gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and <jats:italic>FGFR</jats:italic> mRNA overexpression.Trial RegistrationClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\\\"http://www.w3.org/1999/xlink\\\" ext-link-type=\\\"uri\\\" xlink:href=\\\"https://clinicaltrials.gov/study/NCT03473756\\\">NCT03473756</jats:ext-link>\",\"PeriodicalId\":14850,\"journal\":{\"name\":\"JAMA Oncology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":22.5000,\"publicationDate\":\"2024-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JAMA Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1001/jamaoncol.2024.3900\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAMA Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1001/jamaoncol.2024.3900","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer
ImportanceThe 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).ObjectiveTo 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 ParticipantsThe 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.InterventionsPatients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days.Main Outcomes and MeasuresPrimary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab.ResultsAmong 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT03473756
期刊介绍:
JAMA Oncology is an international peer-reviewed journal that serves as the leading publication for scientists, clinicians, and trainees working in the field of oncology. It is part of the JAMA Network, a collection of peer-reviewed medical and specialty publications.