Jung Hyun Ae, Park Sehhoon, Sun Jong-Mu, Lee Se-Hoon, Ahn Jin Seok, Ahn Myung-Ju, Park Keunchil
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Biology (Basel). 2020 Oct 7;9(10):326. doi: 10.3390/biology9100326.
Approximately 10% of the epidermal growth factor receptor () mutations in non-small-cell lung cancer (NSCLC) are uncommon mutations. Although the efficacy of second (2G) or third generation (3G) tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8-13.5), 11.7 months (95% CI: 6.6-16.7), 7.7 months (95% CI: 4.9-17.4), and 5.0 months (95% CI: 3.7-6.1) for major uncommon mutation (G719X, L861Q), compound mutation with major mutation (Del 19 or exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9-34.2), 28.8 (95% CI: 24.4-33.4), 13.5 months (95% CI: 7.4-27.8), and 9.4 months (95% CI: 3.4-10.5) for major uncommon mutation (G719X), compound mutation with major mutation (Del 19 or exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6-16.9), and 37.5 months (95% CI: 35.4-39.6) for common mutation-positive NSCLC. After failing 1L -TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G -TKI after failing the first-line -TKI, the ORR and PFS for 3G -TKI were 80% and 8.9 months (95% CI: 8.0-9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8-39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common mutations. T790M was detected in 28.6% of the uncommon mutation-positive patients for whom prior 1G/2G -TKIs failed and underwent repeat biopsy at the time of progression.
非小细胞肺癌（NSCLC）中约10%的表皮生长因子受体（EGFR）突变是罕见突变。尽管第二代（2G）或第三代（3G）EGFR酪氨酸激酶抑制剂（EGFR-TKIs）在罕见EGFR突变患者中的疗效已得到证实，但仍需进一步研究以确定罕见EGFR突变阳性NSCLC的最佳治疗方法。本研究回顾性调查了2011年1月至2019年12月在韩国首尔三星医疗中心的罕见EGFR突变阳性NSCLC患者的治疗模式和结局。在研究期间，2121例EGFR突变阳性NSCLC患者接受第一代（1G，吉非替尼或厄洛替尼）或2G EGFR-TKI（阿法替尼）作为一线（1L）全身治疗。其中，135例（6.4%）患者存在罕见EGFR突变。在135例患者中，54例（40%，54/135）患者存在与主要EGFR突变重叠的突变。1L EGFR-TKI的客观缓解率（ORR）为63.3%。主要罕见EGFR突变（G719X、L861Q）、与主要EGFR突变的复合突变（Del19或外显子21 p.L858R）、其他复合突变和其他罕见突变的中位无进展生存期（PFS）分别为8.6个月（95%CI：3.8-13.5）、11.7个月（95%CI：6.6-16.7）、7.7个月（95%CI：4.9-17.4）和5.0个月（95%CI：3.7-6.1）。主要罕见EGFR突变（G719X）、与主要EGFR突变的复合突变（Del19或外显子21 p.L858R）、其他复合突变和其他罕见突变的中位总生存期（OS）分别为25.6个月（16.9-34.2）、28.8个月（95%CI：24.4-33.4）、13.5个月（95%CI：7.4-27.8）和9.4个月（95%CI：3.4-10.5）。常见EGFR突变阳性NSCLC的缓解率、中位PFS和OS分别为63.3%、16.3个月（95%CI：15.6-16.9）和37.5个月（95%CI：35.4-39.6）。1L EGFR-TKI治疗失败后，44.9%（35/78）检测到T790M的患者进行了重复组织或液体活检，其中10/35（28.6%）患者检测到T790M。一线EGFR-TKI治疗失败后使用后续3G EGFR-TKI，3G EGFR-TKI的ORR和PFS分别为80%和8.9个月（95%CI：8.0-9.8）。这些患者的中位OS为34.6个月（95%CI：29.8-39.4）。罕见（尤其是其他复合突变和其他罕见突变）EGFR突变患者的ORR、PFS和OS比常见EGFR突变患者更差。在先前1G/2G EGFR-TKIs治疗失败且疾病进展时接受重复活检的罕见EGFR突变阳性患者中，28.6%检测到T790M。
