Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity.
Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity.
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Poziotinib治疗EGFR 20号外显子突变型NSCLC：临床疗效、耐药机制以及插入位置对药物敏感性的影响
DOI：
10.1016/j.ccell.2022.06.006
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发表时间：
2022-07-11
期刊：
影响因子：
50.3
通讯作者：
Heymach, John, V
中科院分区：
文献类型：
--
作者：
Elamin, Yasir Y.;Robichaux, Jacqulyne P.;Carter, Brett W.;Altan, Mehmet;Tran, Hai;Gibbons, Don L.;Heeke, Simon;Fossella, Frank, V;Lam, Vincent K.;Le, Xiuning;Negrao, Marcelo, V;Nilsson, Monique B.;Patel, Anisha;Vijayan, R. S. K.;Cross, Jason B.;Zhang, Jianjun;Byers, Lauren A.;Lu, Charles;Cascone, Tina;Feng, Lei;Luthra, Rajyalakshmi;San Lucas, Francis A.;Mantha, Geeta;Routbort, Mark;Blumenschein, George, Jr.;Tsao, Anne S.;Heymach, John, V
我们报道了一项II期研究，对50名EGFR外显子20点突变或插入的晚期非小细胞肺癌患者进行了泊齐奥替尼(NCT03066206)治疗。这项研究达到了它的主要终点，研究人员和盲目独立审查的确认客观反应率(ORR)分别为32%和31%，中位无进展生存期为5.5个月。利用临床前研究，在计算机模拟和分子动力学模拟中，我们发现泊佐替尼的敏感性高度依赖于插入位置，近环插入(氨基酸A767到P772)比远环插入更敏感，这一观察结果在临床上得到证实，近环和远环的ORR值分别为46%和0%(p=0.0015)。获得性耐药的可能机制包括EGFR T790M、MET扩增和上皮向间充质转化(EMT)。我们的数据表明，poziotinib在EGFR外显子20突变的NSCLC中是活性的，尽管这种活性受到插入位置的影响。Elamin等人。显示泊齐奥替尼在EGFR外显子20突变的非小细胞肺癌中是活性的。Poziotinib的活性受外显子20插入位置的影响，近环插入比远环插入更敏感。Poziotinib获得性耐药是通过EGFR依赖和独立的机制介导的。
We report a phase II study of 50 advanced NSCLC patients with point mutations or insertions in EGFR exon 20 treated with poziotinib (NCT03066206). The study achieved its primary endpoint, with a confirmed objective response rate (ORR) of 32% and 31% by investigator and blinded independent review, respectively, with a median progression-free survival of 5.5 months. Using preclinical studies, in silico modelling and molecular dynamics simulations, we found that poziotinib sensitivity was highly dependent on the insertion location, with near loop insertions (amino acids A767 to P772) being more sensitive than far loop insertions, an observation confirmed clinically with an ORR of 46% and 0% observed in near vs far loop, respectively (p=0.0015). Putative mechanisms of acquired resistance included EGFR T790M, MET amplifications, and epithelial to mesenchymal transition (EMT). Our data demonstrate that poziotinib is active in EGFR exon 20 mutant NSCLC, although this activity is impacted by insertion location. Elamin et al. show that poziotinib is active in EGFR exon 20 mutant non-small cell lung cancer. The activity of poziotinib is impacted by insertion location in exon 20 with near loop insertion being more sensitive than far loop insertions. Poziotinib acquired resistance is mediated via EGFR-dependent and independent mechanisms.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
4.6
作者：
Kim TM;Lee KW;Oh DY;Lee JS;Im SA;Kim DW;Han SW;Kim YJ;Kim TY;Kim JH;Han H;Kim WH;Bang YJ
通讯作者：
Bang YJ
DOI：
10.1016/j.jtho.2018.03.035
发表时间：
2018-08
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Lisberg A;Cummings A;Goldman JW;Bornazyan K;Reese N;Wang T;Coluzzi P;Ledezma B;Mendenhall M;Hunt J;Wolf B;Jones B;Madrigal J;Horton J;Spiegel M;Carroll J;Gukasyan J;Williams T;Sauer L;Wells C;Hardy A;Linares P;Lim C;Ma L;Adame C;Garon EB
通讯作者：
Garon EB
DOI：
10.1158/1078-0432.ccr-15-3101
发表时间：
2016-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gainor JF;Shaw AT;Sequist LV;Fu X;Azzoli CG;Piotrowska Z;Huynh TG;Zhao L;Fulton L;Schultz KR;Howe E;Farago AF;Sullivan RJ;Stone JR;Digumarthy S;Moran T;Hata AN;Yagi Y;Yeap BY;Engelman JA;Mino-Kenudson M
通讯作者：
Mino-Kenudson M
影响因子：
11.2
作者：
Kosaka T;Tanizaki J;Paranal RM;Endoh H;Lydon C;Capelletti M;Repellin CE;Choi J;Ogino A;Calles A;Ercan D;Redig AJ;Bahcall M;Oxnard GR;Eck MJ;Jänne PA
通讯作者：
Jänne PA