Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Clinical Research Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
BMC Cancer. 2024 Jun 11;24(1):715. doi: 10.1186/s12885-024-12479-0.
Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs.
This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively.
Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively.
Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted.
NCT04507906 August 11, 2020.
免疫检查点抑制剂（ICI）耐药是 NSCLC 患者未满足的主要医疗需求。血管内皮生长因子（VEGF）抑制可能逆转抑制性微环境并恢复对后续 ICI 的敏感性。
这是一项单臂、Ib/IIa 期研究，包括剂量探索（A 部分）和扩展（B 部分）队列。招募了 ICI 耐药的 NSCLC 患者，接受安罗替尼（一种多靶点酪氨酸激酶抑制剂）口服（21 天周期的第 1 至 14 天）和纳武利尤单抗（每 3 周 360mg，静脉注射），21 天为一个治疗周期。第一个 21 天治疗周期为安全性观察期（Ib 期），随后为 II 期扩展队列。主要目标分别为推荐的 II 期剂量（A 部分）、安全性（B 部分）和客观缓解率（B 部分）。
2020 年 11 月至 2022 年 3 月，共筛选了 34 例患者，纳入了 21 例符合条件的患者（A 部分 6 例）。安罗替尼的推荐剂量为 12mg/天（14 天给药，7 天停药），纳武利尤单抗为 360mg/每 3 周。所有接受治疗的患者均报告了任何原因的不良事件（AE）和与治疗相关的不良事件（TRAEs）。2 例患者（9.5%）发生 3 级 TRAE。未观察到 4 级或更高级别的 AE。4 例患者发生严重 AE。由于 TRAE，有 6 例患者中断了安罗替尼治疗，4 例患者中断了纳武利尤单抗治疗。客观缓解率（ORR）和疾病控制率（DCR）分别为 19.0%和 76.2%。中位 PFS 和 OS 分别为 7.4 个月（95%CI，4.3-NE）和 15.2 个月（95%CI，12.1-NE）。
本研究表明，安罗替尼联合纳武利尤单抗具有可管理的安全性和有前景的疗效信号。需要进一步的研究。
NCT04507906 2020 年 8 月 11 日。
