Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined.
Implications for practice: Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.
摘要
针对表皮生长因子受体 (EGFR) 的分子疗法已对进展期非小细胞肺癌 (NSCLC) 的治疗产生了深远的影响。有关使用 EGFR 酪氨酸激酶抑制剂 (EGFR-TKI) 和抗 EGFR 单克隆抗体 (mAb) 抑制 EGFR 在鳞状细胞 NSCLC (sqNSCLC) 中的应用, 在未知肿瘤是否 EGFR 突变的患者中仍然存有争议。近期一项 meta 分析纳入了具有足够统计学效能进行组织学亚组分析的抑制 EGFR 治疗的随机临床试验, 此外, 还要求纳入患者组织学为鳞癌, 并且能够充分地再次回顾 sqNSCLC 中的 EGFR 治疗。在未经选择的不适合接受化疗的 sqNSCLC 患者中, EGFR-TKI 治疗是一种优于安慰剂及最佳支持治疗的有效治疗选择。在随机临床试验中, EGFR-TKI一线和二线治疗改善了无进展生存, 并且在二线治疗中改善了总生存 (OS)。在符合化疗标准的患者中, meta 分析和近期的 SQUIRE sqNSCLC 研究 (化疗± necitumumab) 均显示, 与单用化疗相比, 化疗联合抗 EGFR mAb 方案作为一线治疗改善了 OS。在对诱导化疗有治疗反应的 sqNSCLC 患者中, 使用厄洛替尼维持治疗推迟了疾病进展, 并且可能改善疾病稳定患者的生存。在二线治疗中, meta 分析显示化疗与 EGFR-TKI 治疗的生存转归相似, 而 EGFR-TKI 二线治疗的耐受性更好一些。鉴于 LUX-Lung 8 研究 (阿法替尼vs.厄洛替尼) 获得了阳性结果, 新一代 EGFR-TKI 疗法可能进一步为一线化疗失败的 sqNSCLC 患者带来获益。EGFR 是未经选择/EGFR 野生型肺鳞癌患者的有效靶向治疗方案。近期免疫检查点抑制剂获批用于二线治疗进展期 sqNSCLC 并且已作为新的标准治疗, 新的联合疗法有望提高治疗有效性和改善持续肿瘤控制。由于更多的靶向药物获得批准, 有必要对包含一个抗 EGFR 药物的联合方案进行评价, 同时也应确定最佳的靶向治疗顺序。The Oncologist 2016;21:205–213
对临床实践的提示: 抗表皮生长因子受体 (EGFR) 治疗在未经选择/野生型 EGFR 鳞状细胞非小细胞肺癌 (NSCLC) 患者中仍然存有争议。近期的 meta 分析和仅纳入鳞状细胞 NSCLC 的 EGFR 抑制剂研究中, 已克服了早期临床试验的检验效能局限性, 已能够为抗 EGFR 疗法在鳞状细胞 NSCLC 中的使用提供有力证据。随着免疫疗法在鳞状细胞 NSCLC 二线治疗中的获批, 新的联合方案有望改善有效性和肿瘤持续控制。但现有二线靶向疗法的最佳使用时机和治疗顺序仍然有待明确。本综述针对组织学为鳞癌的患者, 分析了在 NSCLC 中开展的 EGFR 抑制剂随机临床试验和针对这些临床试验的 meta 分析。
Keywords: Epidermal growth factor receptor; Meta-analysis; Monoclonal antibodies; Non-small cell lung cancer; Small molecule; Squamous.
©AlphaMed Press.