Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 432, PO Box 301402, 1500 Holcombe Boulevard, Houston, TX 77030, USA.
Department of Thoracic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Cell. 2022 Jul 11;40(7):754-767.e6. doi: 10.1016/j.ccell.2022.06.006.
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.
我们报告了一项针对 50 名接受波齐替尼治疗的 EGFR 外显子 20 点突变或插入的晚期非小细胞肺癌（NSCLC）患者的 II 期研究（NCT03066206）。该研究达到了主要终点，研究者评估的确认客观缓解率（ORR）分别为 32%和 31%，中位无进展生存期为 5.5 个月。通过临床前研究、计算建模和分子动力学模拟，我们发现波齐替尼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，这一观察结果在临床中得到了证实，近环和远环插入的 ORR 分别为 46%和 0%（p = 0.0015）。获得性耐药的潜在机制包括 EGFR T790M、MET 扩增和上皮-间充质转化（EMT）。我们的数据表明，波齐替尼在 EGFR 外显子 20 突变型 NSCLC 中具有活性，尽管这种活性受到插入位置的影响。
