安罗替尼或吉非替尼分别联合信迪利单抗对KRAS阳性晚期肺腺癌的疗效观察

Efficacy of anlotinib or gefitinib combined with sintilimab in patients with KRAS positive advanced lung adenocarcinoma

摘要:

目的 探讨安罗替尼或吉非替尼分别联合信迪利单抗对鼠类肉瘤病毒癌基因（KRAS）阳性晚期肺腺癌的治疗效果。方法 选取2020年1月至2022年6月濮阳油田总医院84例KRAS阳性晚期肺腺癌患者，随机数字表法分为A组、B组各42例。A组采用安罗替尼联合信迪利单抗治疗，B组采用吉非替尼联合信迪利单抗治疗，以3周为1个周期，持续治疗3个周期。比较两组近期临床疗效，观察治疗前后血清肿瘤标志物［癌胚抗原（CEA）、细胞角蛋白19片段（CYFRA21-1）、胃泌素释放肽前体（ProGRP）及神经元特异烯醇化酶（NSE）］、T细胞免疫指标（CD4⁺、CD8⁺及CD4⁺/CD8⁺）变化，统计药物不良反应发生情况及生存情况。结果 A组失访1例，最终纳入41例；B组失访1例，中途退出1例，最终纳入40例。两组近期临床疗效比较差异有统计学意义（P<0.05）；B组患者疾病控制率为87.50%，高于A组（68.29%）（P<0.05）；治疗后两组血清CEA、CYFRA21-1、ProGRP及NSE水平较治疗前降低（P<0.05），CD4⁺、CD4⁺/CD8⁺较治疗前升高（P<0.05），CD8⁺较治疗前降低（P<0.05）；治疗后B组血清CEA、CYFRA21-1、ProGRP及NSE水平低于A组（P<0.05），CD4⁺、CD4⁺/CD8⁺高于A组（P<0.05），CD8⁺低于A组（P<0.05）；B组皮肤反应发生率高于A组（P<0.05），手足综合征发生率低于A组（P<0.05），两组白细胞减少症、贫血、血小板减少症、食欲不振、恶心呕吐、腹泻、肝损伤、甲状腺功能减退及高血压发生率比较，差异无统计学意义（P>0.05）；Kaplan-Meier生存曲线分析显示，B组无进展生存率、总生存率均高于A组（P<0.05）；B组无进展生存期、总生存期中位数分别为［8.5（5.5，10.5）］个月、［11.0（9.5，11.5）］个月，均长于A组［7.0（4.5，9.5）］个月、［9.5（7.0，11.0）］个月（P<0.05）。结论 KRAS阳性晚期肺腺癌治疗中，相较于信迪利单抗联合安罗替尼，信迪利单抗联合吉非替尼治疗的效果更理想，可提升疾病控制率，降低血清肿瘤标志物水平，改善T细胞免疫功能及生存情况，不良反应以轻中度（1/2级）为主，经对症处理后恢复，有一定安全性。

Abstract:

Objective To investigate the efficacy of anlotinib or gefitinib combined with sintilimab in the treatment of Kirsten rat sarcoma viral oncogene homolog (KRAS) positive advanced lung adenocarcinoma.Methods From January 2020 to June 2022, 84 patients with KRAS positive advanced lung adenocarcinoma were selected and divided into group A and group B with 42 patients in each group by random number table method. Group A was treated with anlotinib combined with sintilimab, and group B was treated with gefitinib combined with sintilimab in a 3-week cycle for 3 consecutive cycles. The recent clinical efficacy of the two groups was compared, the changes of serum tumor markers [carcino-embryonic antigen (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), pro-gastrin-releasing peptide (ProGRP) and neuron-specific enolase (NSE)] and T cell immune indicators (CD4⁺, CD8⁺ and CD4⁺/CD8⁺) before and after treatment were observed, and the occurrence and survival of adverse drug reactions were counted.Results Group A lost 1 case to follow-up, and finally included 41 cases. In group B, 1 case was lost to follow-up, 1 case dropped out midway, and 40 cases were finally included. Comparison of recent clinical efficacy between the two groups showed statistically significant difference (P<0.05). The disease control rate of group B was 87.50%, which was higher than that of group A (68.29%) (P<0.05). After treatment, serum CEA, CYFRA21-1, ProGRP and NSE levels in the two groups were decreased compared with before treatment (P<0.05), CD4⁺, CD4⁺/CD8⁺ were increased compared with before treatment (P<0.05), and CD8⁺ were decreased compared with before treatment (P<0.05). After treatment, the serum CEA, CYFRA21-1, ProGRP and NSE levels in group B were lower than those in group A (P<0.05), CD4⁺, CD4⁺/CD8⁺ were higher than those in group A (P<0.05), and CD8⁺ were lower than those in group A (P<0.05). The incidence of skin reaction in group B was higher than that in group A (P<0.05), and the incidence of hand-foot syndrome was lower than that in group A (P<0.05). There was no significant difference in the proportion of leukopenia, anemia, thrombocytopenia, loss of appetite, nausea and vomiting, diarrhea, liver injury, hypothyroidism and hypertension between the two groups (P>0.05). Kaplan-Meier survival curve analysis showed that progression-free survival and overall survival in group B were higher than those in group A (P<0.05). The median progression-free survival and overall survival of group B were 8.5(5.5, 10.5) months and 11.0(9.5, 11.5) months, respectively, which were longer than those of group A [7.0(4.5, 9.5) months and 9.5(7.0, 11.0) months] (P<0.05).Conclusion In the treatment of KRAS positive advanced lung adenocarcinoma, compared with sintilimab combined with anlotinib, sintilimab combined with gefitinib has a better therapeutic effect, which can increase the disease control rate, reduce the level of serum tumor markers, and improve T cell immune function and survival, the adverse reactions are mainly mild to moderate (grade 1/2), and are recovered after symptomatic treatment, with certain safety.