Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Transl Lung Cancer Res. 2016 Feb;5(1):92-4. doi: 10.3978/j.issn.2218-6751.2015.07.19.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60-70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGFR TKI with activity against the activating EGFR mutation, the T790M acquired resistance mutation, and relative sparing of the wild-type EGFR. AZD9291 was investigated in a phase I trial with expansion cohorts in patients with disease progression after EGFR TKI. Patients with and without detectable T790M mutations were enrolled in the trial. The ORR in patients with centrally confirmed and without detectable T790M mutations was 61% (95% CI, 52-70%) and 21% (95% CI, 12-34%), respectively. The PFS observed in patients with centrally confirmed and without detectable T790M mutations was 9.6 months (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1-4.3 months), respectively. At the dose for further investigation, 80 mg daily, the rate of all grade 3-5 drug related adverse events was 11%, and the rates of grade 3 diarrhea and rash were 1% and 0%, respectively. The identification of the T790M resistance mutation and the subsequent development of an agent against the mechanism of resistance provide a template for future drug development for acquired resistance to targeted therapy.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）在晚期 EGFR 突变非小细胞肺癌中的客观缓解率（ORR）约为 60-70%，中位无进展生存期（PFS）约为 10-13 个月。在 EGFR TKI 进展后对肿瘤活检的研究表明，50-60%的 EGFR 突变 NSCLC 出现了 EGFR 外显子 20 T790M 突变，这是获得性耐药的机制。AZD9291 是一种第三代不可逆的 EGFR TKI，对激活的 EGFR 突变、T790M 获得性耐药突变以及野生型 EGFR 的相对保留均有活性。AZD9291 在一项 I 期临床试验中进行了研究，该试验在 EGFR TKI 治疗后疾病进展的患者中进行了扩展队列。招募了有和没有检测到 T790M 突变的患者参加试验。经中心确认有和没有检测到 T790M 突变的患者的 ORR 分别为 61%（95%CI，52-70%）和 21%（95%CI，12-34%）。经中心确认有和没有检测到 T790M 突变的患者的 PFS 分别为 9.6 个月（95%CI，8.3-未达到）和 2.8 个月（95%CI，2.1-4.3 个月）。在进一步研究的剂量 80mg 每日，所有 3-5 级药物相关不良事件的发生率为 11%，3 级腹泻和皮疹的发生率分别为 1%和 0%。T790M 耐药突变的鉴定以及随后针对耐药机制的药物的开发为针对靶向治疗获得性耐药的未来药物开发提供了模板。
