口服泛成纤维细胞生长因子受体抑制剂罗加替尼此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 期研究中证明了令人鼓舞的安全性和有效性。与程序性细胞死亡 1 配体 1 (PD-L1) 抑制剂 atezolizumab 联合治疗不适合接受顺铂治疗的 FGFR mRNA 阳性、局部晚期/转移性 UC 患者。 FORT-2 非随机临床试验是一项开放标签、单组、该多中心研究于 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。符合条件的患者患有局部晚期/转移性 UC，且 FGFR1/3 mRNA 过度表达，并且不适合接受基于顺铂的化疗。数据分析于2022年7月至2022年9月完成。患者接受罗加替尼600毫克或罗加替尼800毫克，每天两次，联合静脉注射阿替利珠单抗1200毫克，每21天一次。主要终点包括安全性、耐受性和推荐的2期剂量（RP2D） ）罗加替尼联合atezolizumab。在筛选的153名患者中，73名（48%）患有FGFR1/3 mRNA过表达的肿瘤，37名患者入组并接受治疗（中位年龄[范围]，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 名患者 (62%) 的腹泻、19 名患者 (51%) 的高磷血症和 15 名患者 (41%) 的疲劳。 27 名患者 (73%) 报告了 3 级或以上 TEAE，报告了 4 名 5 级 TEAE，但与治疗无关。 RP2D 为 rogaratinib 600 mg 与 atezolizumab 1200 mg 组合。在 RP2D 时，罗加替尼 600 mg 组的总体缓解率为 53.8%，其中 4 名患者（15%）获得完全缓解； 12 名应答者 (86%) 没有 FGFR3 基因改变，11 名应答者 (79%) 的 PD-L1 表达较低。 在这项 1b 期非随机临床试验中，罗加替尼加阿特珠单抗表现出可控的安全性，没有出现意外的安全信号。在低 PD-L1 肿瘤中观察到这种组合在 RP2D 上的功效，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 过表达的患者具有广泛的潜在益处。ClinicalTrials.gov 标识符：NCT03473756。

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.