Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations
Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations
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DOI：
10.1016/j.lungcan.2018.11.039
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发表时间：
2019-01-01
期刊：
影响因子：
5.3
通讯作者：
Soejima, Kenzo
中科院分区：
文献类型：
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作者：
Hasegawa, Hanako;Yasuda, Hiroyuki;Soejima, Kenzo
目的：表皮生长因子受体(EGFR)突变阳性肺癌在非小细胞肺癌(NSCLC)中占有重要地位。在非小细胞肺癌中，大约4%-10%的EGFR突变是EGFR外显子20的插入突变，据报道与对EGFR酪氨酸激酶抑制剂(EGFR-TKI)治疗的抵抗有关。携带这些突变的非小细胞肺癌患者很少接受EGFR-TKI治疗。材料与方法：检测了A763_Y764insFQEA、Y764_V765insHH、A767_V769dupASV和D770_N771insNPG。用野生型或突变EGFR的BA/F3细胞体外检测阿法替尼或奥西美替尼与西妥昔单抗联合治疗的疗效。将携带EGFR A767_V769dupASV或Y764_V765insHH的BALB/c-nu雌性小鼠皮下注射100万个携带EGFR A767_V769dupASV或Y764_V765insHH的BA/F3细胞，观察联合治疗的体内疗效。结果：体外联合治疗对几个EGFR外显子20插入突变有轻微但显著的相加效应(P<；0.05)。对于EGFR A767_V769dupASV和EGFR Y764_V765insHH，西妥昔单抗和阿法替尼单独治疗对肿瘤的形成没有明显的抑制作用，但阿法替尼和西妥昔单抗联合治疗对肿瘤生长有显著的抑制作用(P<；0.05)，并且没有明显的体重减轻和皮疹。结论：联合治疗对几个EGFR外显子20插入突变的抑制作用比单独使用任何一种方法都要强。西妥昔单抗可潜在地提高阿法替尼或奥西美替尼在EGFR外显子20插入突变的非小细胞肺癌中的疗效。
Objectives: Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4-10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations.Materials and methods: The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH.Results: We observed a mild but significant (P < 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P < 0.05) tumor growth inhibition without significant body weight loss or skin rash.Conclusion: The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.