David Geffen School of Medicine at University of California Los Angeles/TRIO-US Network, Los Angeles, USA.
LungenClinic, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany.
ESMO Open. 2023 Aug;8(4):101580. doi: 10.1016/j.esmoop.2023.101580. Epub 2023 Jun 28.
Ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) over placebo + ERL (PBO + ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes.
Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and postdiscontinuation follow-up. EGFR and co-occurring/treatment-emergent (TE) genomic alterations in ctDNA were analyzed using Guardant360 NGS platform.
In those with valid baseline samples, detectable activating EGFR alterations in ctDNA (aEGFR+) were associated with shorter PFS [aEGFR+: 12.7 months (n = 255) versus aEGFR-: 22.0 months (n = 131); hazard ratio (HR) = 1.87, 95% confidence interval (CI) 1.42-2.51]. Irrespective of detectable/undetectable baseline aEGFR, RAM + ERL was associated with longer PFS versus PBO + ERL [aEGFR+: median PFS (mPFS) = 15.2 versus 11.1 months, HR = 0.63, 95% CI 0.46-0.85; aEGFR-: mPFS = 22.1 versus 19.2 months, HR = 0.80, 95% CI 0.49-1.30]. Baseline alterations co-occurring with aEGFR were identified in 69 genes, most commonly TP53 (43%), EGFR (other than aEGFR; 25%), and PIK3CA (10%). PFS was longer in RAM + ERL, irrespective of baseline co-occurring alterations. Clearance of baseline aEGFR by C4 was associated with longer PFS (mPFS = 14.1 versus 7.0 months, HR = 0.481, 95% CI 0.33-0.71). RAM + ERL improved PFS outcomes, irrespective of aEGFR mutation clearance. TE gene alterations were most commonly in EGFR [T790M (29%), other (19%)] and TP53 (16%).
Baseline aEGFR alterations in ctDNA were associated with shorter mPFS. RAM + ERL was associated with improved PFS outcomes, irrespective of detectable/undetectable aEGFR, co-occurring baseline alterations, or aEGFR+ clearance by C4. aEGFR+ clearance by C4 was associated with improved PFS outcomes. Monitoring co-occurring alterations and aEGFR+ clearance may provide insights into mechanisms of EGFR tyrosine kinase inhibitor resistance and the patients who may benefit from intensified treatment schedules.
雷莫芦单抗联合厄洛替尼（RAM+ERL）在表皮生长因子受体（EGFR）突变型转移性非小细胞肺癌（EGFR+ mNSCLC；NCT02411448）的 III 期 RELAY 研究中显示出优于安慰剂+厄洛替尼（PBO+ERL）的无进展生存期（PFS）。下一代测序（NGS）用于鉴定循环肿瘤 DNA（ctDNA）中具有临床意义的改变，并探讨其对治疗结果的影响。
符合条件的 EGFR+ mNSCLC 患者以 1:1 的比例随机分配接受厄洛替尼（150mg/天）加 RAM（10mg/kg）/PBO 每 2 周一次。在基线、第 4 周期（C4）和停药后随访时前瞻性采集液体活检。使用 Guardant360 NGS 平台分析 ctDNA 中的 EGFR 和同时发生/治疗后（TE）基因组改变。
在具有有效基线样本的患者中，ctDNA 中可检测到的激活型 EGFR 改变（aEGFR+）与较短的 PFS 相关[aEGFR+：12.7 个月（n=255）与 aEGFR-：22.0 个月（n=131）；危险比（HR）1.87，95%置信区间（CI）1.42-2.51]。无论基线 aEGFR 是否可检测/不可检测，RAM+ERL 与 PBO+ERL 相比均与较长的 PFS 相关[aEGFR+：中位 PFS（mPFS）15.2 个月与 11.1 个月，HR 0.63，95%CI 0.46-0.85；aEGFR-：mPFS 22.1 个月与 19.2 个月，HR 0.80，95%CI 0.49-1.30]。在 69 个基因中发现了与 aEGFR 同时发生的改变，最常见的是 TP53（43%）、EGFR（除 aEGFR 外；25%）和 PIK3CA（10%）。无论基线同时发生的改变如何，RAM+ERL 均可延长 PFS。C4 时基线 aEGFR 的清除与较长的 PFS 相关（mPFS 14.1 个月与 7.0 个月，HR 0.481，95%CI 0.33-0.71）。无论 aEGFR 突变清除情况如何，RAM+ERL 均可改善 PFS 结局。TE 基因改变最常见于 EGFR [T790M（29%），其他（19%）]和 TP53（16%）。
ctDNA 中的基线 aEGFR 改变与较短的 mPFS 相关。RAM+ERL 与改善的 PFS 结果相关，无论是否可检测到/不可检测到 aEGFR、同时发生的基线改变或 C4 时 aEGFR+的清除情况如何。C4 时 aEGFR+的清除与改善的 PFS 结果相关。监测同时发生的改变和 aEGFR+的清除可能有助于了解 EGFR 酪氨酸激酶抑制剂耐药的机制以及可能从强化治疗方案中获益的患者。
