一些局部晚期/转移性非小细胞肺癌（NSCLC）患者对抗 programmed cell death protein 1（PD-1）/抗 programmed death-ligand 1（PD-L1）治疗反应不良，结合其他药物可能有所改善。本次开放标签的多中心、Ⅰb期试验研究了对综合谱选择性酪氨酸激酶抑制剂 sitravatinib 和抗-PD-1抗体 tislelizumab 进行联合治疗。本研究纳入了局部晚期/转移性 NSCLC 患者（A、B、F、H 和 I 队列；每组 n=22-24）。A 组和 F 组包括曾接受系统治疗的患者，分别患有抗 PD-(L) 1 难治/耐药的非鳞癌型（A 组）或鳞癌型（F 组）疾病；B 组包括曾接受系统治疗，患有抗 PD-(L) 1 初治的非鳞癌型疾病的患者；H 和 I 组包括无先前转移性疾病系统治疗史、无先前抗 PD-(L) 1/免疫治疗的 PD-L1 阳性非鳞癌型（H 组）或鳞癌型（I 组）组织学的患者。患者每天口服 sitravatinib 120 毫克，每隔三周静脉注射 tislelizumab 200 毫克，直至研究退出、疾病进展、不可接受的毒性或死亡。主要终点为在所有接受治疗的患者中（N=122）的安全/耐受性。次要终点包括研究者评估的肿瘤反应和无进展生存期（PFS）。随访中位数为10.9个月（范围：0.4-30.6）。98.4%的患者出现与治疗相关的不良事件(TRAEs)，其中51.6%的患者出现≥3级 TRAEs。TRAEs导致23.0%的患者停止使用其中任何一种药物。A、F、B、H和I组的整体应答率分别为8.7%（n/N：2/23；95% CI：1.1%到28.0%）、18.2%（4/22；95% CI：5.2%到40.3%）、23.8%（5/21；95% CI：8.2%到47.2%）、57.1%（12/21；95% CI：34.0%到78.2%）和30.4%（7/23；95% CI：13.2%到52.9%）。A组中的应答持续时间未达到中位数，其余组中的应答持续时间范围从6.9到17.9个月。78.3-90.9%的患者达到了疾病控制。中位 PFS 范围从4.2个月（A 组）到11.1个月（H 组）。在局部晚期/转移性 NSCLC 患者中，sitravatinib 加 tislelizumab 对大多数患者来说是可耐受的，没有出现新的安全信号，整体安全性与这些药物已知的安全性质相符。观察到了所有队列的客观反应，包括对系统和抗 PD-(L) 1 治疗初步反应的患者或患有抗 PD-(L) 1 耐药/难治疾病的患者。结果支持在选择的 NSCLC 群体中进一步研究。NCT03666143.©作者(或其雇主) 2023年。在CC BY-NC下重新使用，不得商业再利用。由BMJ出版

Some patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) respond poorly to anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) treatments. Combination with other agents may improve the outcomes. This open-label, multicenter, phase 1b trial investigated the combination of sitravatinib, a spectrum-selective tyrosine kinase inhibitor, plus anti-PD-1 antibody tislelizumab.Patients with locally advanced/metastatic NSCLC were enrolled (Cohorts A, B, F, H, and I; N=22-24 per cohort). Cohorts A and F included patients previously treated with systemic therapy, with anti-PD-(L)1-resistant/refractory non-squamous (cohort A) or squamous (cohort F) disease. Cohort B included patients previously treated with systemic therapy, with anti-PD-(L)1-naïve non-squamous disease. Cohorts H and I included patients without prior systemic therapy for metastatic disease, no prior anti-PD-(L)1/immunotherapy, with PD-L1-positive non-squamous (cohort H) or squamous (cohort I) histology. Patients received sitravatinib 120 mg orally one time per day plus tislelizumab 200 mg intravenously every 3 weeks, until study withdrawal, disease progression, unacceptable toxicity, or death. The primary endpoint was safety/tolerability among all treated patients (N=122). Secondary endpoints included investigator-assessed tumor responses and progression-free survival (PFS).Median follow-up was 10.9 months (range: 0.4-30.6). Treatment-related adverse events (TRAEs) occurred in 98.4% of the patients, with ≥Grade 3 TRAEs in 51.6%. TRAEs led to discontinuation of either drug in 23.0% of the patients. Overall response rate was 8.7% (n/N: 2/23; 95% CI: 1.1% to 28.0%), 18.2% (4/22; 95% CI: 5.2% to 40.3%), 23.8% (5/21; 95% CI: 8.2% to 47.2%), 57.1% (12/21; 95% CI: 34.0% to 78.2%), and 30.4% (7/23; 95% CI: 13.2% to 52.9%) in cohorts A, F, B, H, and I, respectively. Median duration of response was not reached in cohort A and ranged from 6.9 to 17.9 months across other cohorts. Disease control was achieved in 78.3-90.9% of the patients. Median PFS ranged from 4.2 (cohort A) to 11.1 months (cohort H).In patients with locally advanced/metastatic NSCLC, sitravatinib plus tislelizumab was tolerable for most patients, with no new safety signals and overall safety profiles consistent with known profiles of these agents. Objective responses were observed in all cohorts, including in patients naïve to systemic and anti-PD-(L)1 treatments, or with anti-PD-(L)1 resistant/refractory disease. Results support further investigation in selected NSCLC populations.NCT03666143.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.