阿帕替尼联合EGFR-TKI一线治疗EGFR敏感突变的晚期非鳞非小细胞肺癌的疗效和安全性分析

Efficacy and safety of apatinib plus EGFR-TKI as a first-line treatment for advanced non-squamous non-small cell lung cancer with activating EGFR mutations

目的观察阿帕替尼联合表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)一线治疗EGFR敏感突变的晚期非鳞非小细胞肺癌(nsNSCLC)的疗效及不良反应。方法拟计划入组2016年8月至2018年8月本院初治伴EGFR敏感突变的Ⅲb~Ⅳ期nsNSCLC患者20例,给予甲磺酸阿帕替尼联合EGFR-TKI治疗直至疾病进展(PD)或不良反应无法耐受停药,采用RECIST 1.1版和NCI-CTCAE 4.0版标准评价疗效和安全性,根据随访数据进行生存分析。结果入组过程中期因3级及以上不良反应发生率高达88.3%(5/6),于2017年8月中止研究,共入组患者6例,其中男性4例、女性2例,年龄范围55~83岁,中位年龄69岁;Ⅲb期1例,Ⅳ期5例;接受阿帕替尼联合吉非替尼4例、阿帕替尼联合埃克替尼2例。6例患者中,持续联合用药2例的总有效率(ORR)为100%,中位无进展生存期(PFS)和总生存期(OS)分别为17.6和32.8个月,余4例患者联合用药后因3级及以上不良反应需要临床干预停用阿帕替尼后单用EGFR-TKI治疗,ORR为50%,中位PFS和OS分别为15.0和25.6个月。最常见的3~4级不良反应为手足综合征1例(16.7%)、口腔黏膜炎1例(16.7%)、食欲减退2例(33.3%)、肝功能异常1例(16.7%)、肾功能异常1例(16.7%)和高血压1例(16.7%)。结论EGFR敏感突变的晚期nsNSCLC患者阿帕替尼联合EGFR-TKI用药后PFS、OS可疑获益,但不良反应明显,不推荐其作为一线方案治疗伴EGFR敏感突变的晚期nsNSCLC。联合用药显著增加患者3~4级不良反应,主要为手足综合征、口腔黏膜炎、食欲减退、肝功能不全。低龄(<65岁)患者联合用药可能受益,可尝试在临床使用。

Objective To observe the efficacy and safety of apatinib plus epidermal grouth factor receptor tyrosine kinase inhibitor(EGFR-TKI)as a first-line treatment for advanced non-squamous non-small cell lung cancer(nsNSCLC)with activating epidermal growth factor receptor(EGFR)mutations.Methods From August 2016 to August 2018,it was planned to enroll 20 patients with stageⅢb orⅣnsNSCLC with sensitive EGFR mutations.All patients were treated with apatinib in combination with EGFR-TKI drugs until disease progression,intolerant toxicity or patient withdrawal.RECIST version 1.1 and NCI-CTCAE version 4.0 were used to evaluate the efficacy and safety,and the survival was analyzed according to the follow-up data.Results In the middle of the enrollment process,the incidence of grade 3 and above adverse reactions was as high as 88.3%(5/6),and the study was suspended in August 2017.There were 4 males and 2 females,with the median age of 69(range 55-83),and 1 case of stage IIIb and 5 cases of stageⅣ.Four patients received apatinib combined with gefitinib,and two received apatinib with icotinib.Among 6 patients,2 patients received the continuous doublet regime until the disease progressed with overall response rate(ORR)of 100%,median progression-free survival(PFS)of 17.6 months and median overall survival(OS)of 32.8 months.For the other 4 cases with grade 3 adverse reactions,apatinib was stopped and treated with EGFR-TKI continuously,and ORR was 50%with the median PFS of 15.0 months and median OS of 25.6 months.The most common treatment-related grade 3 to 4 adverse events were hand-foot syndrome in 1 case(16.7%),stomatitis in 1 case(16.7%),anorexia in 2 case(33.3%),liver dysfunction in 1 case(16.7%),renal dysfunction in 1 case(16.7%)and hypertension in 1 case(16.7%).Conclusion Apatinib plus EGFR-TKI as the first-line treatment for advanced nsNSCLC with EGFR mutations had suspected benefits in PFS and OS,but adverse events limited its use.The combination significantly increased the incidence of grade 3 and 4 adverse reactions that mainly included hand-foot syndrome,stomatitis,anorexia and liver dysfunction.However,age might be a beneficial factor,which needs to be confirmed by further studies.