[The efficacy and prognostic factors of immunotherapy in advanced non-small cell lung cancer patients with different driver gene mutations].

Objective: To explore the efficacy and prognostic factors of immunotherapy in advanced non-small cell lung cancer (NSCLC) patients with different driver gene mutations. Methods: Medical records of advanced NSCLC patients who harbored driver gene mutations (EGFR, KRAS, ALK and etc.) and received PD-1 inhibitors in Henan Cancer Hospital from April 2016 to May 2021 were collected. Treatment patterns, progression free survival (PFS), overall survival (OS) and prognostic factors of patients with driver gene mutations were estimated. Results: A total of 120 patients were included. There were 70 males and 50 females, with a median age [M(Q1,Q3)] of 57 (50, 65) years. Of these, 52 patients harbored KRAS mutations, 42 patients harbored EGFR mutations, 16 patients harbored ERBB2 mutations, 5 patients harbored MET mutations or amplifications, 5 patients harbored ROS-1 mutations, 2 patients harbored BRAF mutations, and the last 2 patients harbored ALK and RET mutations, respectively. The PFS and OS [M (95%CI)] were 6.4 (5.1-7.8) and 31.2 (22.0-40.3) months in 120 participated patients. Patients with KRAS mutations showed the greatest survival benefit from Immune checkpoint inhibitors (ICIs) with the PFS of 9.7 (4.8-14.6) months and OS of 31.2 (19.4-50.6) months. They mostly received the first-line (34.6%, 18/52) and second-line (38.5%, 20/52) ICIs. The PFS and OS of EGFR mutant patients were 3.9 (1.8-6.1) months and 18.0 (12.1-23.8) months, respectively. They tended to receive ICIs after resistance to EGFR-tyrosine kinase inhibitors (TKIs), and the proportion of second-, third-, fourth or further-line drugs was 38.1% (16/42), 11.9% (5/42), and 47.6% (20/42), respectively. PD-L1 expression level (negative vs ≥50% positive: HR=3.710, 95%CI: 1.372-10.031, P=0.010; 1%-49% positive vs ≥50% positive: HR=2.738, 95%CI: 0.841-8.912, P=0.094), age (every additional year: HR=0.957, 95%CI: 0.933-0.982, P=0.001) and different driver mutations status (EGFR vs KRAS: HR=2.676, 95%CI: 1.317-5.436, P=0.006; ERBB2 vs KRAS: HR=3.411, 95%CI: 1.493-7.792, P=0.004; other mutations vs KRAS: HR=0.727, 95%CI: 0.322-1.643, P=0.444) were prognostic factors for PFS. While PD-L1 expression level (negative vs ≥50% positive: HR=2.305, 95%CI: 0.748-7.103, P=0.146; 1%-49% positive vs ≥50% positive: HR=1.286, 95%CI: 0.337-4.913, P=0.713), and treatment lines of ICIs (first-line vs ≥ third-line: HR=0.322, 95%CI: 0.114-0.914, P=0.033; second-line vs ≥ third-line: HR=0.375, 95%CI: 0.178-0.789, P=0.010) were prognostic factors for OS. Conclusions: KRAS mutant NSCLC patients mostly receive ICIs at the front line, and have best survival benefits from immunotherapy. While EGFR mutant NSCLC patients tend to receive ICIs at the back line, and obtain reasonable survival benefits. PD-L1 expression level, age, and different driver mutations status are prognostic factors for PFS, and PD-L1 expression level and treatment lines of ICIs are prognostic factors for OS.目的： 探讨不同驱动基因突变晚期非小细胞肺癌（NSCLC）患者接受免疫治疗的疗效及预后影响因素。 方法： 回顾性收集2016年4月至2021年5月河南省肿瘤医院接受程序性细胞死亡受体1（PD-1）抑制剂治疗、驱动基因（EGFR、KRAS、ALK等）阳性、晚期NSCLC患者的资料，分析不同驱动基因突变状态的患者接受免疫治疗的模式、无进展生存期（PFS）和总生存期（OS）及预后影响因素。 结果： 本研究共纳入120例患者，男70例，女50例，年龄［M（Q1，Q3）］为57（50，65）岁。其中KRAS突变患者52例、EGFR突变患者42例、ERBB2突变患者16例、MET突变或扩增患者5例、ROS-1融合患者5例、BRAF突变患者2例、ALK及RET突变患者各1例。120例患者的PFS［M（95%CI）］为6.4（5.1~7.8）个月，OS为31.2（22.0~40.3）个月。KRAS突变肺癌患者接受免疫治疗的生存获益最大，PFS为9.7（4.8~14.6）个月，OS为31.2（19.4~50.6）个月，且免疫治疗多为一线（34.6%，18/52）、二线（38.5%，20/52）治疗。EGFR突变患者PFS、OS分别为3.9（1.8~6.1）个月、18.0（12.1~23.8）个月，一般在EGFR酪氨酸激酶抑制剂（TKIs）耐药后接受免疫治疗，二、三、四线及以上治疗线数患者比例分别为38.1%（16/42）、11.9%（5/42）、47.6%（20/42）。程序性细胞死亡受体配体1（PD-L1）表达水平（以表达水平≥50%为参照，阴性：HR=3.710，95%CI：1.372~10.031，P=0.010；表达水平1%~49%：HR=2.738，95%CI：0.841~8.912，P=0.094）、年龄（每增加1岁，HR=0.957，95%CI：0.933~0.982，P=0.001）、不同驱动基因突变（以KRAS突变为参照，EGFR突变：HR=2.676，95%CI：1.317~5.436，P=0.006；ERBB2突变：HR=3.411，95%CI：1.493~7.792，P=0.004；其他突变：HR=0.727，95%CI：0.322~1.643，P=0.444）为PFS的影响因素。PD-L1表达水平（以表达水平≥50%为参照，阴性：HR=2.305，95%CI：0.748~7.103，P=0.146；表达水平1%~49%：HR=1.286，95%CI：0.337~4.913，P=0.713）、免疫治疗线数（以≥三线为参照，一线：HR=0.322，95%CI：0.114~0.914，P=0.033；二线：HR=0.375，95%CI：0.178~0.789，P=0.010）为OS的影响因素。 结论： KRAS突变肺癌患者多在前线接受免疫治疗，生存获益最多，EGFR突变肺癌患者多在后线接受免疫治疗，患者能获得较好的生存获益。PD-L1表达水平、年龄、不同驱动基因突变为PFS的影响因素，PD-L1表达水平、免疫治疗线数为OS的影响因素。.