*僅供醫(yī)學(xué)專業(yè)人士閱讀參考
罕見突變也有“特效藥”了
EGFR突變是中國肺腺癌人群最常檢出的可靶向驅(qū)動基因變異。近年來，隨著對腫瘤分子生物學(xué)研究的不斷深入，臨床研究者對EGFR突變患者進一步細分。EGFR突變常發(fā)生在18-21號外顯子，最常見的突變類型為19號外顯子缺失突變和21號外顯子L858R點突變，可達到80%以上。除此之外最常見的便是EGFR 20號外顯子插入突變（EGFR exon 20ins），約占總體EGFR突變肺腺癌人群的6%，與經(jīng)典突變患者的臨床特征類似，常發(fā)生于女性、不吸煙的肺腺癌患者中[1-3]。
然而，不同于常見突變患者對酪氨酸激酶抑制劑（TKI）敏感，EGFR exon 20ins患者對早期TKI表現(xiàn)為原發(fā)耐藥，對一代TKI吉非替尼/厄洛替尼的客觀緩解率（ORR）為0%，對二代TKI阿法替尼的ORR為11%，中位無進展生存期（PFS）小于2個月[4]。不過有研究顯示，三代TKI奧希替尼對EGFR exon 20ins有一定的效果，ORR為25%，中位PFS為9.7個月[5]。
參考文獻：
[1]Sabari JK,Heymach JV,Sandy B.Hitting the Right Spot:Advances in the Treatment of NSCLC With Uncommon EGFR Mutations.J Natl Compr Canc Netw.2021;19(Suppl_2):S1-S11.doi:10.6004/jnccn.2021.0200.
[2]Oxnard GR,Lo PC,Nishino M,et al.Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.J Thorac Oncol.2013;8(2):179-84.doi:10.1097/JTO.0b013e3182779d18.
[3]Kobayashi Y,Mitsudomi T.Not all epidermal growth factor receptor mutations in lung cancer are created equal:Perspectives for individualized treatment strategy.Cancer Sci.2016;107(9):1179-86.doi:10.1111/cas.12996.
[4]Robichaux JP,Elamin YY,Tan Z,et al.Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.Nat Med.2018;24(5):638-646.doi:10.1038/s41591-018-0007-9.
[5]Piotrowska Z,Wang Y,Sequist LV,et al.ECOG-ACRIN 5162:a phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions[abstract].J Clin Oncol 2020;38(Suppl):Abstract 9513.
[6]Wang J,Wang B,Chu H,Yao Y.Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations.Onco Targets Ther.2016;9:3711-26.doi:10.2147/OTT.S106399.
[7]Robichaux JP,Elamin YY,Tan Z,et al.Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.Nat Med.2018;24(5):638-646.doi:10.1038/s41591-018-0007-9.
[8]Vasconcelos PENS,Kobayashi IS,Kobayashi SS,Costa DB.Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations.JTO Clin Res Rep.2021;2(3):100105.doi:10.1016/j.jtocrr.2020.100105.
[9]NCCN Guidelines Version 1.2022 Non-Small Cell Lung Cancer.
[10]Yun J,Lee SH,Kim SY,et al.Antitumor Activity of Amivantamab(JNJ-61186372),an EGFR-MET Bispecific Antibody,in Diverse Models of EGFR Exon 20 Insertion-Driven NSCLC.Cancer Discov.2020;10(8):1194-1209.doi:10.1158/2159-8290.CD-20-0116.
[11]Vijayaraghavan S,Lipfert L,Chevalier K,et al.Amivantamab(JNJ-61186372),an Fc Enhanced EGFR/cMet Bispecific Antibody,Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis.Mol Cancer Ther.2020;19(10):2044-2056.doi:10.1158/1535-7163.
[12]Sabari JK et al.,Amivantamab in post-platinum EGFR exon 20 insertion mutation non-small cell lung cancer.J Thorac Oncol 2021;16(3):S108-S109.
[13]Doebele X,Riely GJ,Spira K,et al.First report of safety,PK,and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788(AP32788)in non-small cell lung cancer[abstract].J Clin Oncol 2018;36(Suppl):Abstract 9015.
[14]Neal J et al.,Safety,PK,and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 in NSCLC.J Thorac Oncol 2018;13(10):S599.
[15]Janne PA,Neal JW,Camidge DR,et al.Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions[abstract].J Clin Oncol 2019;37(Suppl):Abstract 9007.
[16]Zhou C,Ramalingam S,Li B,et al.Mobocertinib in NSCLC with EGFR exon 20 insertions:results from the EXCLAIM and pooled platinum-pretreated patient populations.J Thorac Oncol2021;16:S108.
[17]Le X,Goldman JW,Clarke JM,et al.Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients[abstract].J Clin Oncol 2020;38(Suppl):Abstract 9514.
