Medical Oncology Service, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain.
Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
Ann Oncol. 2024 Sep;35(9):805-816. doi: 10.1016/j.annonc.2024.05.541. Epub 2024 Jun 26.
BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.
背景：Amivantamab-lazertinib 显著延长了携带表皮生长因子受体（EGFR）突变的晚期非小细胞肺癌（NSCLC）患者的无进展生存期（PFS），与奥希替尼相比[风险比（HR）0.70；P < 0.001]，包括有脑转移史的患者（HR 0.69）。同时，伴有 TP53 共突变、可检测到循环肿瘤 DNA（ctDNA）、基线肝转移以及治疗期间无 ctDNA 清除的患者预后较差。我们评估了这些高危亚组的结果。
方法：这项分析纳入了在 MARIPOSA 研究中接受治疗初治、EGFR 突变的晚期 NSCLC 患者，随机分配至接受 amivantamab-lazertinib（n = 429）或奥希替尼（n = 429）治疗。通过 Guardant360 CDx 对基线血 ctDNA 进行下一代测序（NGS）来识别致病性改变。采用 Biodesix 液滴数字聚合酶链反应（ddPCR）分析基线和第 3 周期第 1 天（C3D1）的外显子 19 缺失和 L858R ctDNA。
结果：共有 636 名患者（amivantamab-lazertinib，n = 320；奥希替尼，n = 316）可获得用于 NGS 的致病性改变的基线 ctDNA。与奥希替尼相比，amivantamab-lazertinib 改善了伴有 TP53 共突变的患者的中位 PFS（mPFS）[18.2 个月对 12.9 个月；HR 0.65（95%置信区间（CI）0.48-0.87）；P = 0.003]和野生型 TP53 患者的 mPFS[22.1 个月对 19.9 个月；HR 0.75（95% CI 0.52-1.07）]。在 EGFR 突变、ddPCR 检测到基线 ctDNA 的患者中，与奥希替尼相比，amivantamab-lazertinib 显著延长了 mPFS[20.3 个月对 14.8 个月；HR 0.68（95% CI 0.53-0.86）；P = 0.002]。在 C3D1 时无 ctDNA 清除的患者中，与奥希替尼相比，amivantamab-lazertinib 显著改善了 mPFS[16.5 个月对 9.1 个月；HR 0.49（95% CI 0.27-0.87）；P = 0.015]和有清除的患者的 mPFS[16.5 个月对 9.1 个月；HR 0.49（95% CI 0.27-0.87）；P = 0.015]。与奥希替尼相比，在随机分配的患者中，amivantamab-lazertinib 显著延长了伴有[18.2 个月对 11.0 个月；HR 0.58（95% CI 0.37-0.91）；P = 0.017]和不伴有基线肝转移的患者的 mPFS[24.0 个月对 18.3 个月；HR 0.74（95% CI 0.60-0.91）；P = 0.004]。
结论：Amivantamab-lazertinib 有效地克服了高危特征的影响，为携带 EGFR 突变的晚期 NSCLC 患者提供了一种有前途的新治疗标准。
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