表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)是不可切除的EGFR突变阳性(EGFRm)非小细胞肺癌(NSCLC)的一线治疗标准。然而,10-20%的EGFRm+NSCLC患者有不常见的EGFR变异,定义为除L858R取代或外显子19缺失以外的突变。与具有L858R或外显子19缺失突变的NSCLC相比,具有不常见EGFR突变的NSCLC可能显示出对靶向药物的敏感性较低。缺乏NSCLC罕见EGFR突变患者的前瞻性临床试验数据。阿法替尼是第二代TKI,也是食品和药物管理局批准的用于治疗一些更普遍的不常见EGFR突变的唯一药物。我们提供了一系列七例病例报告,描述了阿法替尼治疗的NSCLC患者的临床结果,这些患者具有各种极其罕见的突变,有或没有影响其他基因的共突变。EGFR改变包括化合物突变,P-环αC-螺旋压缩突变,和新的替代突变。我们还提出了一个具有新型EGFR::CCDC6基因融合的NSCLC病例。总的来说,患者对阿法替尼反应良好,包括6名患者在治疗期间的放射学部分反应。三名患者的反应是持久的。出现的病例与越来越多的临床和临床前证据相一致,这些证据表明NSCLC具有各种不常见的EGFR突变,有或没有共突变,可能对阿法替尼敏感。
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, 10-20% of patients with EGFRm+ NSCLC have uncommon EGFR variants, defined as mutations other than L858R substitutions or exon 19 deletions. NSCLC harboring uncommon EGFR mutations may demonstrate lower sensitivity to targeted agents than NSCLC with L858R or exon 19 deletion mutations. Prospective clinical trial data in patients with NSCLC uncommon EGFR mutations are lacking.
Afatinib is a second-generation TKI and the only Food and Drug Administration-approved drug for some of the more prevalent uncommon EGFR mutations. We present a series of seven
case reports describing clinical outcomes in
afatinib-treated patients with NSCLC harboring a diverse range of extremely rare mutations with or without co-mutations affecting other genes. EGFR alterations included compound mutations, P-loop αC-helix compressing mutations, and novel substitution mutations. We also present a
case with NSCLC harboring a novel EGFR::CCDC6 gene fusion. Overall, the patients responded well to
afatinib, including radiologic partial responses in six patients during treatment. Responses were durable for three patients. The cases presented are in line with a growing body of clinical and preclinical evidence that indicating that NSCLC with various uncommon EGFR mutations, with or without co-mutations, may be sensitive to
afatinib.