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

中文翻译：

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Rogaratinib 联合 Atezolizumab 治疗顺铂不合格的 FGFR RNA 过表达尿路上皮癌患者


重要性口服泛成纤维细胞生长因子受体抑制剂 rogaratinib 先前在一项针对过表达 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有效性。目的评价罗加替尼联合程序性细胞死亡 1 配体 1 （PD-L1） 抑制剂阿替利珠单抗在顺铂不合格的 FGFR mRNA 阳性、局部晚期/转移性 UC.Design 患者中的安全性、药代动力学和初步疗效，环境和参与者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 日在亚洲的 30 个中心进行， 欧洲和北美。符合条件的患者患有局部晚期/转移性 UC 伴 FGFR1/3 mRNA 过表达，不适合以顺铂为基础的化疗。数据分析于 2022 年 7 月至 2022 年 9 月完成。干预患者接受罗加替尼 600 mg 或罗加替尼 800 mg，每日两次联合静脉注射阿替利珠单抗 1200 mg，每 21 天一次。主要结局和测量主要终点包括 rogaratinib 联合 atezolizumab 的安全性、耐受性和推荐的 2 期剂量 （RP2D）。结果在筛选的 153 例患者中，73 例 （48%） 患有 FGFR1/3 mRNA 过表达的肿瘤，37 例患者入组并接受治疗 （中位 [范围] 年龄，75.0 [47.0-85.0] 岁;32 [87%] 男性）。最常见的治疗中出现的不良事件 （TEAE） 包括 23 例患者 （62%） 腹泻，19 例 （51%） 高磷血症和 15 例 （41%） 疲劳。27 例患者 （73%） 报告了 3 级或更高级别的 TEAE，并报告了 4 例 5 级 TEAE，尽管与治疗无关。RP2D 为 rogaratinib 600 mg 联合 atezolizumab 1200 mg。 在 RP2D 时，rogaratinib 600 mg 组的总缓解率为 53.8%，包括 4 例患者 （15%） 完全缓解;12 例应答者 （86%） 没有 FGFR3 基因改变，11 例 （79%） PD-L1 表达较低。结论和相关性在这项 1b 期非随机临床试验中，rogaratinib 联合 atezolizumab 显示出可控的安全性，没有意外的安全信号。在 PD-L1 水平较低的肿瘤中观察到这种组合在 RP2D 的疗效，并且不依赖于 FGFR3 基因改变，这表明对局部晚期/转移性 UC 和 FGFR mRNA 过表达患者具有广泛的潜在益处。试验注册临床试验。gov 标识符： NCT03473756