免疫联合抗血管生成治疗在难治性非小细胞肺癌中的应用价值

Value of immune combined anti-angiogenic therapy in refractory non-small cell lung cancer

目的 研究发现抗血管生成制剂可提高免疫检查点抑制剂的免疫应答、增强抗肿瘤活性,尚无相关研究探索免疫联合抗血管生成治疗在难治性非小细胞肺癌(non-small cell cancer, NSCLC)中的应用。方法 回顾性收集2019年1月至2021年6月于郑州大学第一附属医院经多线治疗失败后应用免疫检查点抑制剂联合抗血管生成药物治疗的61例NSCLC患者的临床资料,评价近期疗效,记录不良反应,通过复诊或电话对患者进行随访,计算无进展生存期(progression free survival, PFS)和总体生存期(overall survival, OS)。结果 临床分期Ⅲ期11例(18.0%),Ⅳ期50例(82.0%),鳞癌22例(36.1%),腺癌31例(50.8%)。中位治疗周期5个(范围1~13),客观缓解率(Objective Response Rate, ORR)21.3%,疾病控制率(Disease Control Rate, DCR)54.1%。中位随访时间9个月(范围3~25个月),中位PFS为3个月(95%CI 2.291~3.709),中位OS为9.0个月(95%CI 7.222~10.778)。亚组分析PD-L1 (programmed death receptor ligand 1)阳性与阴性患者的ORR和DCR(29.2%vs 17.4%2=0.908 P=0.341,58.3%vs 52.2%χ^(2)=0.180 P=0.671),PFS和OS(4.2 vs 3.0个月χ^(2)=1.143 P=0.285,10.0 vs 8.0个月χ^(2)=2.797 P=0.094),EGFR (epidermal growth factor receptor)阴性和阳性患者的ORR和DCR(19.4%vs 6.2%χ^(2)=0.641 P=0.423,52.8%vs 37.5%χ^(2)=1.036 P=0.309),PFS和OS(2.3 vs 3.0个月χ^(2)=0.026 P=0.871,10.0 vs 8.0个月χ^(2)=1.708 P=0.191),均无统计学差异。86.8%的患者在治疗过程中会发生不良反应,主要是1~2级不良反应,36.1%的患者出现3级以上不良反应,一例出现致死性不良反应事件。结论 免疫联合抗血管生成治疗NSCLC具有一定的临床疗效和可接受的安全性,且疗效与PD-L1表达和是否存在EGFR突变无关,可作为多线治疗失败的难治性NSCLC的治疗选择。

Objective Previous study finds anti-angiogenic agents may help enhance the immune response and anti-tumor activity of immune checkpoint inhibitors. There is no relevant research exploring the application of immune combined antiangiogenic therapy in refractory non-small cell lung cancer(NSCLC). Methods Clinical data of 61 patients with NSCLC treated with immune checkpoint inhibitors combined with anti-angiogenic drugs after multiple lines of failure were retrospectively collected from January 2019 to June 2021 at the First Affiliated Hospital of Zhengzhou University, evaluated short-time efficacy, and recorded the adverse events. Progression Free Survival(PFS) and Overall Survival(OS) were calculated by follow-up at outpatient visits or telephone. Results There were 11(18.0%) cases of stage Ⅲ,50(82.0%) cases of stage Ⅳ,22(36.1%) cases of squamous carcinoma, and 31(50.8%) cases of adenocarcinoma. The median treatment period was 5(range 1 to 13),with an objective response rate(ORR) of 21.3% and a disease control rate(DCR) of 54.1%. The median follow-up time was 9 months(3-25 months),median PFS was 3 months(95%CI 2.291~3.709),and median OS was 9.0 months(95%CI 7.222~10.778). Subgroup analysis in PD-L1 positive vs. negative patients of ORR and DCR(29.2% vs. 17.4%,χ^(2)=0.908,P=0.341,58.3% vs. 52.2%,χ^(2)=0.180,P=0.671),PFS and OS(4.2 vs. 3.0 months, χ^(2)=1.143,P=0.285,10.0 vs. 8.0 months, χ^(2)=2.797,P=0.094),EGFR negative vs. positive patients( 19.4% vs. 6.2%,χ^(2)=0.641,P=0.423,52.8% vs. 37.5%,χ^(2)=1.036,P=0.309),PFS and OS(2.3 vs. 3.0 months, χ^(2)=0.026,P=0.871,10.0 vs. 8.0 months, χ^(2)=1.708,P=0.191), neither statistically different. There were 86.8% of patients experienced adverse reactions during treatment, and 36.1% of patients experienced grade 3 or higher, which recovered after discontinuation or symptomatic treatment, and one had a fatal adverse event.Conclusion Combined immune checkpoint inhibitors and anti-angiogenic agents for the treatment of NSCLC has certain clinical efficacy and acceptable safety, and efficacy was independent of PD-L1 expression and the presence of EGFR mutations, can be a treatment option for patients with refractory NSCLC who have failed multiple lines of therapy.