Shi Xun, Lin Chen, Lou Lishu, He Qiong, Lou Guangyuan, Hong Wei, Shao Lan, Zhao Jun, Gu Cuiping, Yu Xinmin, Jin Ying
Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
Cancer Med. 2025 Sep;14(17):e71191. doi: 10.1002/cam4.71191.
Although immune checkpoint inhibitors (ICIs) have markedly improved first-line management of non-small cell lung cancer (NSCLC), many tumors eventually escape control after anti-PD-(L)1 therapy, leaving a clear therapeutic gap. Preclinical studies and preliminary clinical data suggest that coupling ICIs with anti-angiogenesis therapy can yield complementary antitumor effects. Consequently, we launched this investigation to evaluate the therapeutic benefit and tolerability of sintilimab, a PD-(L)1-blocking monoclonal antibody, together with the oral multi-target anti-angiogenesis agent anlotinib in metastatic NSCLC individuals experiencing progression after first-line PD-(L)1 inhibition.
At Zhejiang Cancer Hospital, we conducted a phase II trial, single-arm, open-label investigation (registration No. NCT04691388). Patients were adults diagnosed with metastatic NSCLC whose disease had advanced after PD-(L)1 blockade; they received sintilimab plus anlotinib on a 21-day cycle. Investigator-assessed objective response rate (ORR) served as the principal efficacy endpoint.
Between March 2021 and January 2024, twenty-nine individuals were recruited (median age 63, range 45-74, 96.6% male). Tumor assessment identified five partial responses (PR) (17.2%), nineteen cases of stable disease (SD) (65.5%) and three progressions (10.3%), yielding an ORR of 17.2% and a disease-control rate (DCR) of 82.8%. The cohort's median progression-free survival (PFS) measured 5.0 months (90% CI, 4.2-7.3), and 41.1% of participants remained progression-free at six months. Overall survival reached a median of 15.1 months (90% CI, 8.6-not yet reached), with an 18-month survival proportion of 44.8%. Grade ≥ 3 treatment-related toxicity was dominated by hypertension, occurring in 10.3% of participants; no patient discontinued therapy or died because of drug-related events.
Sintilimab combined with anlotinib exhibited favorable antitumor activity and tolerable toxicity in post-anti-PD-(L)1 therapy of metastatic NSCLC patients, supporting further randomized controlled trials.
ClinicalTrials.gov: NCT04691388. Registered December 31, 2020.
尽管免疫检查点抑制剂（ICIs）显著改善了非小细胞肺癌（NSCLC）的一线治疗，但许多肿瘤在接受抗PD-(L)1治疗后最终仍会逃脱控制，留下明显的治疗缺口。临床前研究和初步临床数据表明，将ICIs与抗血管生成治疗相结合可产生互补的抗肿瘤作用。因此，我们开展了这项研究，以评估程序性死亡受体1（PD-1）/程序性死亡配体1（PD-L1）阻断单克隆抗体信迪利单抗与口服多靶点抗血管生成药物安罗替尼联合应用于一线PD-(L)1抑制治疗后病情进展的转移性NSCLC患者的治疗获益和耐受性。
在浙江省肿瘤医院，我们进行了一项II期单臂开放标签试验（注册号：NCT04691388）。患者为成年转移性NSCLC患者，其疾病在接受PD-(L)1阻断治疗后进展；他们接受信迪利单抗联合安罗替尼治疗，每21天为一个周期。研究者评估的客观缓解率（ORR）作为主要疗效终点。
2021年3月至2024年1月，共招募了29例患者（中位年龄63岁，范围45-74岁，96.6%为男性）。肿瘤评估发现5例部分缓解（PR）（17.2%）、19例疾病稳定（SD）（65.5%）和3例疾病进展（PD）（10.3%），ORR为17.2%，疾病控制率（DCR）为82.8%。该队列的中位无进展生存期（PFS）为5.0个月（90%CI，4.2-7.3），41.1%的参与者在6个月时仍未出现疾病进展。总生存期达到中位15.1个月（90%CI，8.6-未达到），18个月生存率为44.8%。≥3级治疗相关毒性以高血压为主，发生在10.3%的参与者中；没有患者因药物相关事件停药或死亡。
信迪利单抗联合安罗替尼在转移性NSCLC患者抗PD-(L)1治疗后显示出良好的抗肿瘤活性和可耐受的毒性，支持进一步开展随机对照试验。
ClinicalTrials.gov：NCT046913
