ALK突变晚期非小细胞肺癌靶向治疗耐药后帕博利珠单抗治疗的新探索

doi:10.3760/cma.j.issn.1007-1245.2024.06.005

摘要/Abstract

摘要：

目的　探索间变性淋巴瘤激酶（ALK）突变晚期非小细胞肺癌（NSCLC）靶向治疗耐药后帕博利珠单抗治疗的效果。方法　本方案采用前瞻性、对照、单中心、随机、单盲临床研究方法设计。选择2020年3月至2022年7月在西安高新医院就诊的95例ALK突变晚期NSCLC靶向治疗耐药后患者，以随机数字表法分为对照组和试验组。对照组入组47例，脱落2例，最终45例纳入分析；试验组入组48例，脱落2例，最终46例纳入分析。对照组男29例，女16例；年龄（56.85±8.67）岁；ⅢB期12例，Ⅳ期33例；鳞癌12例，腺癌33例。试验组男26例，女20例；年龄（55.02±8.23）岁；ⅢB期15例，Ⅳ期31例；鳞癌10例，腺癌36例。对照组接受阿来替尼治疗，试验组在对照组基础上接受帕博利珠单抗治疗。21 d为1个治疗周期，两组均治疗3个周期。比较两组治疗前后基质金属蛋白酶-9（MMP-9）、血清细胞角蛋白19片段抗原21-1（CYFRA21-1）、神经元特异性烯醇化酶（NSE）、糖类抗原9（CA9）、内皮抑素（ES）、血管内皮生长因子（VEGF）、自然杀伤（NK）细胞、CD8+、CD4+水平，临床疗效，药物不良反应；记录两组患者生存情况。采用独立样本t检验、配对t检验、χ²检验。结果　治疗后，两组CYFRA21-1、NSE、CA9、MMP-9、VEGF、CD8+水平均低于治疗前（均P<0.05），且试验组均低于对照组（均P<0.05）；两组ES、CD4+、NK水平均高于治疗前（均P<0.05），且试验组均高于对照组（均P<0.05）。试验组总有效率高于对照组［78.26%（36/46）比57.78%（26/45）］（χ²=4.396，P=0.036）。两组药物不良反应总发生率比较差异无统计学意义（χ²=0.385，P=0.535）。随访1年，试验组失访1例，对照组失访2例，随访率为97.70%。试验组的1年总生存率为55.56%（25/45），对照组的1年总生存率为34.88%（15/43）。两组患者总生存期（OS）曲线比较差异有统计学意义（Log-rank χ²=7.805，P=0.005）。结论　帕博利珠单抗治疗ALK突变晚期NSCLC靶向治疗耐药后患者疗效显著，可改善免疫功能，降低肿瘤标志物水平，提高生存率，改善血管生成调节因子水平，且不会明显增加药物不良反应的发生率。

关键词:

非小细胞肺癌, 晚期, 间变性淋巴瘤激酶突变, 帕博利珠单抗, 阿来替尼, 安全性

Abstract:

Objective　To explore the efficacy of pembrolizumab treatment after resistance to targeted therapy in patients with advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) mutation. Methods　It was a prospective, controlled, single-center, randomized, single-blind clinical study. Ninety-five patients with advanced NSCLC with ALK mutation who were resistant to targeted therapy were selected from Xi'an Gaoxin Hospital from March 2020 to July 2022, and were divided into a control group and an experimental group by the random number table method. In the control group, 47 cases were enrolled, 2 cases were shed, and 45 cases were finally included in the analysis. In the experimental group, 48 cases were enrolled, 2 cases were shed, and 46 cases were finally included in the analysis. The control group included 29 males and 16 females, aged (56.85±8.67) years; there were 12 cases of stage III B and 33 cases of stage IV; there were 12 cases of squamous cell carcinoma and 33 cases of adenocarcinoma. The experimental group included 26 males and 20 females, aged (55.02±8.23) years; there were 15 cases of stage III B and 31 cases of stage IV; there were 10 cases of squamous cell carcinoma and 36 cases of adenocarcinoma.The control group received alectinib treatment, and the experimental group received pembrolizumab treatment on the basis of the control group. With 21 days as a treatment cycle, both groups were treated for 3 cycles. The levels of matrix metalloproteinase-9 (MMP-9), serum cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), neuron-specific enolase (NSE), carbohydrate antigen 9 (CA9), endostatin (ES), vascular endothelial growth factor (VEGF), natural killer (NK) cells, CD8+, and CD4+ before and after treatment, clinical efficacy, and adverse drug reactions were compared between the two groups; the survival conditions of the two groups were recorded. Independent sample t test, paired t test, and χ² test were used. Results　After treatment, the levels of CYFRA21-1, NSE, CA9, MMP-9, VEGF, and CD8+ in both groups were lower than those before treatment (all P<0.05), and those in the experimental group were lower than those in the control group (all P<0.05); the levels of ES, CD4+, and NK cells in both groups were higher than those before treatment (all P<0.05), and those in the experimental group were higher than those in the control group (all P<0.05). The total effective rate of the experimental group was higher than that of the control group [78.26% (36/46) vs. 57.78% (26/45)] (χ²=4.396, P=0.036). There was no statistically significant difference in the total incidence of adverse drug reactions between the two groups (χ²=0.385, P=0.535). After 1 year of follow-up, 1 case was lost in the experimental group and 2 cases in the control group, with a follow-up rate of 97.70%. The 1-year overall survival rate of the experimental group was 55.56% (25/45), and that of the control group was 34.88% (15/43). There was a statistically significant difference in the overall survival (OS) curve between the two groups (Log-rank χ²=7.805, P=0.005). Conclusion　Pembrolizumab treatment for ALK-mutated advanced NSCLC after resistance to targeted therapy shows significant efficacy, which can improve the immune function, reduce the tumor marker levels, increases the survival rate, and improve the angiogenesis regulatory factors, without significantly increasing the incidence of adverse drug reactions.

Key words:

Non-small cell lung cancer, Advanced, Anaplastic lymphoma kinase mutation, Pembrolizumab, Alectinib, Safety

程琳魏亚兰田霞.

ALK突变晚期非小细胞肺癌靶向治疗耐药后帕博利珠单抗治疗的新探索 [J]. 国际医药卫生导报, 2024, 30(6): 908-912.

Cheng Lin, Wei Yalan, Tian Xia.

New exploration of pembrolizumab treatment for ALK-mutated advanced non-small cell lung cancer after resistance to targeted therapy [J]. International Medicine and Health Guidance News, 2024, 30(6): 908-912.

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