Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain.
JAMA Oncol. 2024 Nov;10(11):1565-1570. doi: 10.1001/jamaoncol.2024.3900. Epub 2024 Sep 19.
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 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 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 / 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 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 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 gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and mRNA overexpression.
ClinicalTrials.gov Identifier: NCT03473756.
先前的一项 1 期研究表明，口服泛成纤维细胞生长因子受体抑制剂罗加替尼在过度表达信使 RNA（mRNA）的膀胱癌（UC）患者中具有令人鼓舞的安全性和疗效。
评估罗加替尼联合程序性细胞死亡配体 1（PD-L1）抑制剂阿替利珠单抗在不适合顺铂治疗的局部晚期/转移性 UC 患者中的安全性、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 日在亚洲、欧洲和北美的 30 个中心进行。入组标准为局部晚期/转移性 UC 患者，mRNA 过表达且不适合顺铂为基础的化疗。数据分析于 2022 年 7 月至 2022 年 9 月完成。
患者接受罗加替尼 600mg 或罗加替尼 800mg 每日两次联合静脉注射阿替利珠单抗 1200mg，每 21 天一次。
主要终点包括罗加替尼联合阿替利珠单抗的安全性、耐受性和推荐的 2 期剂量（RP2D）。
在 153 例筛选患者中，73 例（48%）肿瘤存在 mRNA 过表达，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%]为男性）。最常见的治疗相关不良事件（TEAE）包括 23 例（62%）腹泻、19 例（51%）高磷血症和 15 例（41%）疲劳。27 例（73%）患者报告了 3 级或更高级别的 TEAEs，报告了 4 例 5 级 TEAEs，但与治疗无关。RP2D 为罗加替尼 600mg 联合阿替利珠单抗 1200mg。在 RP2D 时，罗加替尼 600mg 组的总体缓解率为 53.8%，包括 4 例（15%）完全缓解；12 名应答者（86%）没有 基因改变，11 名（79%）PD-L1 表达较低。
在这项 1b 期非随机临床试验中，罗加替尼联合阿替利珠单抗具有可管理的安全性，无意外安全性信号。在 RP2D 观察到该联合治疗方案在低 PD-L1 肿瘤中的疗效，且不依赖于 基因改变，这表明该方案可能对局部晚期/转移性 UC 和 mRNA 过表达的患者具有广泛的潜在获益。
ClinicalTrials.gov 标识符：NCT03473756。
