Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation‐Positive Non‐Small Cell Lung Cancer: A Prospective, Single‐Arm, Phase II Study

Abstract

Lessons Learned.

• The findings of this prospective, single‐arm, phase II study showed that neoadjuvant erlotinib was well tolerated and might improve the radical resection rate in patients with stage IIIA‐N2 epidermal growth factor receptor mutation‐positive non‐small cell lung cancer (NSCLC).

• Erlotinib shows promise as a neoadjuvant therapy option in this patient population.

• Next‐generation sequencing may be useful for predicting outcomes with preoperative tyrosine kinase inhibitors (TKIs) in patients with NSCLC.

• Large‐scale randomized controlled trials investigating the role of TKIs in perioperative therapy, combining neoadjuvant and adjuvant treatments to enhance personalized therapy for patients in this precision medicine era, are warranted.

Background.

Information on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as neoadjuvant therapy in non‐small cell lung cancer (NSCLC) is scarce. We evaluated whether neoadjuvant erlotinib improves operability and survival in patients with stage IIIA‐N2 EGFR mutation‐positive NSCLC.

Methods.

We conducted a prospective, single‐arm, phase II study. Patients received erlotinib 150 mg per day for 56 days in the neoadjuvant period. The primary endpoint was the radical resection rate.

Results.

Nineteen patients were included in the final analysis. After erlotinib treatment, 14 patients underwent surgery. The radical resection rate was 68.4% (13/19) with a 21.1% (4/19) rate of pathological downstaging. The objective response rate was 42.1%; 89.5% (17/19) of patients achieved disease control, with a 10.3‐month median disease‐free survival among patients who underwent surgery. Among all 19 patients who received neoadjuvant therapy, median progression‐free survival (PFS) and overall survival were 11.2 and 51.6 months, respectively. Adverse events (AEs) occurred in 36.8% (7/19) of patients, with the most common AE being rash (26.3%); 15.8% experienced grade 3/4 AEs. Quality of life (QoL) improvements were observed after treatment with erlotinib for almost all QoL assessments. Effects of TP53 mutation on prognosis were evaluated in eight patients with adequate tissue samples. Next‐generation sequencing revealed that most patients had a TP53 gene mutation (7/8) in addition to an EGFR mutation. No TP53 mutation, or very low abundance, was associated with longer PFS (36 and 38 months, respectively), whereas high abundance was associated with short PFS (8 months).

Conclusion.

Neoadjuvant erlotinib was well tolerated and may improve the radical resection rate in this patient population. Next‐generation sequencing may predict outcomes with preoperative TKIs.

Translated abstract

经验获取

• 本次前瞻性单组 II 期研究结果显示，埃罗替尼新辅助治疗在 IIIA‐N2 期表皮生长因子受体突变阳性非小细胞肺癌 (NSCLC) 患者中的耐受性良好，可以提高根治性切除率。

• 在此患者群体中，埃罗替尼显示出了作为新辅助治疗选择的希望。

• 对于预测 NSCLC 患者的手术前酪氨酸激酶抑制剂 (TKI) 结果而言，下一代测序可能十分有用。

• 为了在这个精准医疗的时代提高患者的个性化治疗水平，开展旨在调查 TKI 在围术期治疗(新辅助治疗与辅助治疗相结合)中作用的大规模随机对照试验很有必要。

摘要

背景。 关于表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 作为非小细胞肺癌 (NSCLC) 的新辅助治疗的信息十分匮乏。我们对埃罗替尼新辅助治疗能否改进 IIIA‐N2 期 EGFR 突变阳性 NSCLC 患者的可手术性和生存期进行了评估。

方法。 我们进行了一项前瞻性单组 II 期研究。在新辅助治疗期间，患者每天服用埃罗替尼 150 mg，连续给药 56 天。主要终点是根治性切除率。

结果。 最终分析中包含 19 名患者。在埃罗替尼治疗之后，14 名患者接受手术。根治性切除率为 68.4% (13/19)，病理性降级率为 21.1% (4/19)。客观反应率为 42.1%；89.5% (17/19) 的患者病情得到控制，在接受手术的患者中，中位无病生存期为 10.3 个月。在所有接受新辅助治疗的 19 名患者中，中位无进展生存期 (PFS) 和总体生存期分别为 11.2 个月和 51.6 个月。36.8% (7/19) 的患者出现不良反应 (AE)，最常见的 AE 为皮疹 (26.3%)；15.8% 的患者出现 3/4 级 AE。对于几乎所有的生存质量 (QoL) 评估，在治疗后均观察到了 QoL 改善。我们针对 8 名具有适当组织样本的患者评估了 TP53 突变对预后的影响。下一代测序显示，除 EGFR 突变之外，大多数患者均有 TP53 基因突变 (7/8)。无 TP53 突变或极低丰度与较长的 PFS(分别为 36 个月和 38 个月)相关，而高丰度与短 PFS(8 个月)相关。

结论。 埃罗替尼新辅助治疗在此患者群体中的耐受性良好，可以提高根治性切除率。下一代测序可以预测手术前 TKI 的结果。