Department of Respiratory Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
Division of Thoracic Oncology, Hyogo Cancer Center, 13-70, Kitaohji-cho, Akashi, Hyogo 673-8558, Japan.
Lung Cancer. 2018 Oct;124:65-70. doi: 10.1016/j.lungcan.2018.07.031. Epub 2018 Jul 23.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (i.e., EGFR-TKIs) improve the survival of lung cancer patients harboring EGFR mutations. Despite the initial efficacy of EGFR-TKIs, the disease progression caused by acquired resistance to these inhibitors is inevitable. T790M mutations represent a major resistance mechanism to EGFR-TKIs but can be overcome using osimertinib. The IMPRESS trial revealed that the continuation of EGFR-TKI beyond progressive disease (PD) concurrent with platinum-doublet chemotherapy was not beneficial. However, various clinical trials have suggested that EGFR-TKI beyond PD plus single-agent chemotherapy may be a possible treatment strategy.
This study was a single-arm phase II trial. Patients with EGFR-activating mutations (del19 and L858R) that progressed using first-line gefitinib treatment were enrolled and treated with gefitinib beyond PD plus pemetrexed 500 mg/m q3w. The primary endpoint was progression-free survival (PFS). Mutation-biased polymerase chain reaction quenching probe, which is the original method for detecting T790M mutations in cell-free plasma DNA, was used prior to treatment.
Thirty-six patients were enrolled between May 1, 2013, and March 31, 2016. One patient was excluded before starting the treatment. Among the 35 patients, 15 patients had del19 mutations, and 20 patients had L858R mutations; 33 patients were evaluable for response by using radiographic findings. The median PFS was 6.7 months (95% confidence interval: 4.4-7.7 months). Nineteen patients were T790M positive. No significant difference in PFS was found in a subgroup analysis of EGFR mutation status and T790M positivity. All toxicities were tolerable.
Gefitinib plus pemetrexed treatment following relapse using gefitinib in patients with Non-small cell lung cancer harboring EGFR mutations demonstrated preferable PFS with mild toxicity. This combination therapy may be considered for platinum-unfit patients without T790M with disease progression using first-line gefitinib. (This clinical trial was registered in UMIN-CTGR as UMIN000010709).
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（即 EGFR-TKIs）可改善携带 EGFR 突变的肺癌患者的生存。尽管 EGFR-TKIs 最初具有疗效，但这些抑制剂获得性耐药引起的疾病进展是不可避免的。T790M 突变是 EGFR-TKIs 耐药的主要机制，但可通过奥希替尼克服。IMPRESS 试验表明，在疾病进展（PD）期间继续使用 EGFR-TKI 联合铂类双药化疗无益。然而，多项临床试验表明，PD 后继续使用 EGFR-TKI 联合单药化疗可能是一种可行的治疗策略。
这是一项单臂 II 期试验。招募了一线吉非替尼治疗后进展的携带 EGFR 激活突变（del19 和 L858R）的患者，并用吉非替尼联合 PD 后培美曲塞 500mg/m2，每 3 周 1 次进行治疗。主要终点是无进展生存期（PFS）。在治疗前，使用了原始的用于检测细胞游离血浆 DNA 中 T790M 突变的基于突变的聚合酶链反应淬灭探针。
2013 年 5 月 1 日至 2016 年 3 月 31 日期间共招募了 36 名患者，其中 1 名患者在开始治疗前被排除。在 35 名可评估患者中，15 名患者携带 del19 突变，20 名患者携带 L858R 突变；33 名患者可通过影像学结果评估反应。中位 PFS 为 6.7 个月（95%置信区间：4.4-7.7 个月）。19 名患者 T790M 阳性。EGFR 突变状态和 T790M 阳性的亚组分析中，PFS 无显著差异。所有毒性反应均可耐受。
在携带 EGFR 突变的非小细胞肺癌患者中，在使用吉非替尼治疗后复发时，使用吉非替尼联合培美曲塞治疗可获得更好的 PFS，且毒性反应轻微。对于无 T790M 且一线吉非替尼治疗后疾病进展的铂类不耐受患者，可考虑这种联合治疗。（本临床试验在 UMIN-CTGR 注册为 UMIN000010709）。
