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Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity
Cancer Cell ( IF 48.8 ) Pub Date : 2022-07-11 , DOI: 10.1016/j.ccell.2022.06.006 Yasir Y Elamin 1 , Jacqulyne P Robichaux 1 , Brett W Carter 2 , Mehmet Altan 1 , Hai Tran 1 , Don L Gibbons 1 , Simon Heeke 1 , Frank V Fossella 1 , Vincent K Lam 3 , Xiuning Le 1 , Marcelo V Negrao 1 , Monique B Nilsson 1 , Anisha Patel 4 , R S K Vijayan 5 , Jason B Cross 5 , Jianjun Zhang 1 , Lauren A Byers 1 , Charles Lu 1 , Tina Cascone 1 , Lei Feng 6 , Rajyalakshmi Luthra 7 , Francis A San Lucas 7 , Geeta Mantha 7 , Mark Routbort 7 , George Blumenschein 1 , Anne S Tsao 1 , John V Heymach 1
Cancer Cell ( IF 48.8 ) Pub Date : 2022-07-11 , DOI: 10.1016/j.ccell.2022.06.006 Yasir Y Elamin 1 , Jacqulyne P Robichaux 1 , Brett W Carter 2 , Mehmet Altan 1 , Hai Tran 1 , Don L Gibbons 1 , Simon Heeke 1 , Frank V Fossella 1 , Vincent K Lam 3 , Xiuning Le 1 , Marcelo V Negrao 1 , Monique B Nilsson 1 , Anisha Patel 4 , R S K Vijayan 5 , Jason B Cross 5 , Jianjun Zhang 1 , Lauren A Byers 1 , Charles Lu 1 , Tina Cascone 1 , Lei Feng 6 , Rajyalakshmi Luthra 7 , Francis A San Lucas 7 , Geeta Mantha 7 , Mark Routbort 7 , George Blumenschein 1 , Anne S Tsao 1 , John V Heymach 1
Affiliation
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We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in 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, 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 T790M, amplifications, and epithelial-to-mesenchymal transition (EMT). Our data demonstrate that poziotinib is active in exon 20-mutant NSCLC, although this activity is influenced by insertion location.
中文翻译：
Poziotinib 治疗 EGFR 外显子 20 突变 NSCLC：临床疗效、耐药机制以及插入位置对药物敏感性的影响
我们报告了一项 II 期研究，对象为 50 名外显子 20 点突变或插入的晚期非小细胞肺癌 (NSCLC) 患者，接受 Poziotinib 治疗 (NCT03066206)。该研究达到了主要终点，经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。通过临床前研究、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上得到证实在近环和远环中观察到的 ORR 分别为 46% 和 0% (p = 0.0015)。获得性耐药的假定机制包括 T790M、扩增和上皮间质转化 (EMT)。我们的数据表明，poziotinib 在外显子 20 突变 NSCLC 中具有活性，尽管这种活性受到插入位置的影响。
更新日期：2022-07-11
中文翻译：
Poziotinib 治疗 EGFR 外显子 20 突变 NSCLC：临床疗效、耐药机制以及插入位置对药物敏感性的影响
我们报告了一项 II 期研究，对象为 50 名外显子 20 点突变或插入的晚期非小细胞肺癌 (NSCLC) 患者，接受 Poziotinib 治疗 (NCT03066206)。该研究达到了主要终点，经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。通过临床前研究、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上得到证实在近环和远环中观察到的 ORR 分别为 46% 和 0% (p = 0.0015)。获得性耐药的假定机制包括 T790M、扩增和上皮间质转化 (EMT)。我们的数据表明，poziotinib 在外显子 20 突变 NSCLC 中具有活性，尽管这种活性受到插入位置的影响。
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