美国德州大学安德森癌症中心John V. Heymach团队近期取得重要工作进展，他们研究报告了Poziotinib治疗EGFR外显子20突变非小细胞肺癌的临床疗效、耐药机制以及插入位置对药物敏感性的影响。这一研究成果2022年7月11日在线发表于《癌细胞》杂志上。

研究人员报告了一项对50名EGFR 20号外显子点突变或插入的晚期非小细胞肺癌 (NSCLC) 患者进行的II期研究，这些患者接受了poziotinib（NCT03066206）治疗。该研究达到了主要终点，研究者和盲法独立审查确认的客观缓解率（ORR）分别为32%和31%，中位无进展生存期为5.5个月。

使用临床前研究、计算机建模和分子动力学模拟，研究人员发现poziotinib的敏感性高度依赖于插入位置，近环插入（氨基酸A767至P772）比远环插入更敏感，临床观察证实，在近环和远环中观察到的ORR分别为46%和0%（p = 0.0015）。获得性耐药的推定机制包括EGFR T790M、MET扩增和上皮间质转化（EMT）。他们的数据表明，poziotinib在EGFR外显子20突变的NSCLC中具有活性，尽管这种活性受插入位置的影响。

附：英文原文

Title: Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

Author: Yasir Y. Elamin, Jacqulyne P. Robichaux, Brett W. Carter, Mehmet Altan, Hai Tran, Don L. Gibbons, Simon Heeke, Frank V. Fossella, Vincent K. Lam, Xiuning Le, Marcelo V. Negrao, Monique B. Nilsson, Anisha Patel, R.S.K. Vijayan, Jason B. Cross, Jianjun Zhang, Lauren A. Byers, Charles Lu, Tina Cascone, Lei Feng, Rajyalakshmi Luthra, Francis A. San Lucas, Geeta Mantha, Mark Routbort, George Blumenschein, Anne S. Tsao, John V. Heymach

Issue&Volume: 2022/07/11

Abstract: We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in EGFR exon 20 treated with poziotinib (NCT03066206). The study achieved its primary endpoint, with confirmed objective response rates (ORRs) 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 modeling, 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 ORRs of 46% and 0% observed in near versus 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 influenced by insertion location.

DOI: 10.1016/j.ccell.2022.06.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00270-7