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

IF 22.5 1区 医学 Q1 ONCOLOGY JAMA Oncology Pub Date : 2024-09-19 DOI:10.1001/jamaoncol.2024.3900
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
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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. 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引用次数: 0

摘要

重要性口服泛成纤维细胞生长因子受体抑制剂罗加替尼曾在一项针对过表达FGFR信使RNA(mRNA)的尿路上皮癌(UC)患者的1期研究中显示出令人鼓舞的安全性和疗效。目的评估罗加替尼联合程序性细胞死亡 1 配体 1 (PD-L1) 抑制剂阿特珠单抗治疗不符合顺铂治疗条件的 FGFR mRNA 阳性、局部晚期/转移性 UC 患者的安全性、药代动力学和初步疗效。设计、设置和参与者FORT-2非随机临床试验是一项开放标签、单臂、多中心研究,于2018年5月15日至2021年7月16日期间在亚洲、欧洲和北美的30个中心进行。符合条件的患者为局部晚期/转移性 UC,FGFR1/3 mRNA 过表达,且不符合顺铂化疗条件。干预措施患者接受罗加替尼600毫克或罗加替尼800毫克,每天两次,联合静脉注射阿特珠单抗1200毫克,每21天一次。主要结果和测量指标主要终点包括安全性、耐受性以及罗加替尼联合阿特珠单抗的2期推荐剂量(RP2D)。结果在筛选出的153名患者中,73人(48%)的肿瘤存在FGFR1/3 mRNA过表达,37名患者入组并接受治疗(中位年龄[范围]为75.0[47.0-85.0]岁;32人[87%]为男性)。最常见的治疗突发不良事件(TEAEs)包括:23 名患者(62%)出现腹泻,19 名患者(51%)出现高磷血症,15 名患者(41%)出现疲劳。27名患者(73%)报告了3级或更高的TEAE,4名患者报告了5级TEAE,但与治疗无关。RP2D是罗加替尼600毫克联合阿特珠单抗1200毫克。在RP2D时,罗加替尼600毫克组的总应答率为53.8%,其中4例患者(15%)为完全应答;12例应答者(86%)无FGFR3基因改变,11例应答者(79%)PD-L1表达较低。在PD-L1较低的肿瘤中观察到了该组合在RP2D阶段的疗效,并且不依赖于FGFR3基因的改变,这表明局部晚期/转移性UC和FGFR mRNA过表达的患者可能会广泛受益:NCT03473756
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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
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来源期刊
JAMA Oncology
JAMA Oncology Medicine-Oncology
自引率
1.80%
发文量
423
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.
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