Provencio Mariano, Serna-Blasco Roberto, Franco Fabio, Calvo Virgina, Royuela Ana, Auglytė Milda, Sánchez-Hernández Alfredo, de Julián Campayo María, García-Girón Carlos, Dómine Manuel, Blasco Ana, Sánchez José M, Oramas Juana, Bosch-Barrera Joaquim, Sala María Á, Sereno María, Ortega Ana L, Chara Luis, Hernández Berta, Padilla Airam, Coves Juan, Blanco Remedios, Balsalobre José, Mielgo Xabier, Bueno Coralia, Jantus-Lewintre Eloisa, Molina-Vila Miguel Á, Romero Atocha
Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain.
Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain.
Eur J Cancer. 2021 May;149:61-72. doi: 10.1016/j.ejca.2021.02.031. Epub 2021 Apr 5.
Survival data support the use of first-line osimertinib as the standard of care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitors (TKIs) followed by osimertinib for all patients. It is impossible to predict which patients are at high risk of progression, and this constitutes a major limitation of the sequential TKI approach.
A total of 830 plasma samples from 228 patients with stage IV, EGFR-positive NSCLC who were treated with first-line TKIs were analysed by digital polymerase chain reaction (dPCR).
The circulating tumour DNA (ctDNA) levels helped to identify patients with significantly improved survival rate, regardless of the treatment. Patients treated with first- or second-generation TKIs (N = 189) with EGFR mutations in plasma at a mutant allele frequency (MAF) <7% before treatment initiation (low-risk patients) or who were ctDNA negative after 3 or 6 months of treatment and with an MAF <7% at diagnosis (high responders) had two-thirds lower risk of death than patients in the opposite situation (adjusted hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.23-0.64 and HR = 0.22; 95% CI: 0.12-0.42, respectively). The median overall survival (OS) for low-risk patients and high responders treated with first- or second-generation TKIs was 34.2 months and not reached, respectively, regardless of second-line treatment. There were no significant difference in OS between low-risk or high-responder patients treated upfront with osimertinib (N = 39) and those treated under a sequential approach with osimertinib (N = 60). Median OS was not reached in both cases.
Pre-treatment ctDNA levels identify low-risk patients, who may benefit from sequential TKI treatment. Information regarding EGFR mutation clearance can help to improve patient selection.
生存数据支持将一线奥希替尼作为表皮生长因子受体（EGFR）阳性非小细胞肺癌（NSCLC）的标准治疗方案。然而，对于所有患者而言，一线使用奥希替尼是否优于序贯使用第一代或第二代酪氨酸激酶抑制剂（TKIs）后再使用奥希替尼，目前仍不清楚。无法预测哪些患者具有高进展风险，这是序贯TKI治疗方法的一个主要局限性。
对228例接受一线TKIs治疗的IV期EGFR阳性NSCLC患者的830份血浆样本进行数字聚合酶链反应（dPCR）分析。
无论采用何种治疗方法，循环肿瘤DNA（ctDNA）水平有助于识别生存率显著提高的患者。在治疗开始前，血浆中EGFR突变的突变等位基因频率（MAF）<7%的接受第一代或第二代TKIs治疗的患者（N = 189）（低风险患者），或在治疗3或6个月后ctDNA呈阴性且诊断时MAF<7%的患者（高反应者），其死亡风险比处于相反情况的患者低三分之二（调整后风险比[HR]=0.38；95%置信区间[CI]：0.23 - 0.64和HR = 0.22；95% CI：0.12 - 0.42）。无论二线治疗如何，接受第一代或第二代TKIs治疗的低风险患者和高反应者的中位总生存期（OS）分别为34.2个月和未达到。接受一线奥希替尼治疗的低风险或高反应者（N = 39）与序贯使用奥希替尼治疗的患者（N = 60）之间的OS无显著差异。两种情况下的中位OS均未达到。
治疗前ctDNA水平可识别低风险患者，这些患者可能从序贯TKI治疗中获益。关于EGFR突变清除的信息有助于改善患者选择。
