University of Texas MD Anderson Cancer Center, Houston, TX, USA.
University of Chicago Medicine, Chicago, IL, USA.
Eur Urol Oncol. 2024 Aug;7(4):933-943. doi: 10.1016/j.euo.2023.12.001. Epub 2023 Dec 16.
Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC.
The 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1-38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously).
The primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients.
Sitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied.
In this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer.
检查点抑制剂治疗（CPI）已显示出在尿路上皮癌（UC）中具有生存获益；然而，由于耐药性，并非所有患者都能从 CPI 中获益。联合使用酪氨酸激酶抑制剂（TAM）受体的多靶点受体酪氨酸激酶抑制剂司他拉替尼（TYRO3、AXL 和 MERTK）和 VEGFR2，与 CPI 联合使用可能会改善抗肿瘤反应。我们的目的是评估司他拉替尼联合纳武利尤单抗在晚期/转移性 UC 患者中的疗效和安全性。
516-003 试验（NCT03606174）是一项开放标签、多队列的 2 期研究，评估了在八个队列中接受过 CPI、铂类化疗（PBC）或抗体药物偶联物（ADC）治疗的晚期/转移性 UC 患者中司他拉替尼联合纳武利尤单抗的疗效和安全性。共有 244 名患者接受了司他拉替尼联合纳武利尤单抗治疗（中位随访时间 14.1-38.2 个月）。司他拉替尼（游离碱胶囊 120mg 每日一次[QD]或马来酸胶囊 100mg QD）联合纳武利尤单抗（每 2 周 240mg/每 4 周 480mg 静脉注射）。
主要终点为客观缓解率（ORR；RECIST v1.1）。次要终点包括无进展生存期（PFS）和安全性。采用预测概率设计和置信区间方法。在既往接受 PBC 治疗的患者中，CPI 初治患者（n=53）的 ORR 和中位 PFS 分别为 32.1%和 3.9 个月，CPI 耐药患者（n=67）为 14.9%和 3.9 个月，CPI 和 ADC 耐药患者（n=56）为 5.4%和 3.7 个月。在所有队列中，3.3%的患者发生 3 级治疗相关不良事件（TRAEs），3.3%的患者发生 4 级 TRAEs，1 例 TRAE 导致死亡（心力衰竭）。50.4%的患者发生免疫相关不良事件。6.1%的患者因 TRAE 而停止司他拉替尼/纳武利尤单抗治疗。
在研究的八个队列中，司他拉替尼联合纳武利尤单抗治疗晚期/转移性 UC 患者的安全性可管理，但未导致有临床意义的 ORR。
在这项研究中，两种抗癌药物司他拉替尼和纳武利尤单抗的联合使用产生了可管理的副作用，但对膀胱癌患者没有产生有意义的反应。
