Herbst Roy S, John Thomas, Grohé Christian, Goldman Jonathan W, Kato Terufumi, Laktionov Konstantin, Bonanno Laura, Tiseo Marcello, Majem Margarita, Dómine Manuel, Ahn Myung-Ju, Kowalski Dariusz M, Pérol Maurice, Sriuranpong Virote, Özgüroğlu Mustafa, Bhetariya Preetida, Markovets Aleksandra, Rukazenkov Yuri, Muldoon Caitlin, Robichaux Jacqulyne, Hartmaier Ryan, Tsuboi Masahiro, Wu Yi-Long
Medical Oncology and Hematology, Yale School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Department of Medical Oncology and Hematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Nat Med. 2025 Mar 17. doi: 10.1038/s41591-025-03577-y.
Osimertinib-a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor-is recommended as adjuvant therapy for resected stage IB-IIIA epidermal growth factor receptor-mutated non-small-cell lung cancer, based on significant disease-free survival (DFS) and overall survival improvement shown in the previously reported phase 3 ADAURA trial. A trend toward an increased DFS event rate after completion of 3 years adjuvant treatment in ADAURA suggests that some patients may benefit from longer adjuvant osimertinib treatment. We therefore explored whether tumor-informed, circulating tumor DNA-based, molecular residual disease (MRD) could predict recurrence in an exploratory post hoc analysis of 220 patients (n = 112 osimertinib; n = 108 placebo) from ADAURA. MRD preceded imaging DFS events in this study by a median of 4.7 (95% confidence interval, 2.2-5.6) months. DFS and MRD event-free rate at 36 months was 86% versus 36% for patients in the osimertinib versus placebo groups (hazard ratio, 0.23 (95% confidence interval, 0.15-0.36)). In the osimertinib group, DFS or MRD events were detected in 28 (25%) patients; most events occurred following osimertinib cessation (19 of 28, 68%) and within 12 months of stopping osimertinib (11 of 19, 58%). At 24 months after osimertinib, the DFS and MRD event-free rate was 66%. In this study, MRD preceded DFS events in most patients across both arms. DFS and MRD event-free status was maintained for most patients during adjuvant osimertinib treatment and posttreatment follow-up, with most MRD or DFS events occurring after osimertinib treatment discontinuation or completion. MRD detection could potentially identify patients who may benefit from longer adjuvant osimertinib, although this requires clinical confirmation. ClinicalTrials.gov identifier: NCT02511106 .
奥希替尼——一种第三代表皮生长因子受体酪氨酸激酶抑制剂——基于先前报道的3期ADAURA试验中显示的显著无病生存期（DFS）延长和总生存期改善，被推荐用于已切除的IB-IIIA期表皮生长因子受体突变的非小细胞肺癌的辅助治疗。ADAURA试验中3年辅助治疗完成后DFS事件发生率有增加趋势，这表明一些患者可能从更长时间的奥希替尼辅助治疗中获益。因此，我们在一项对ADAURA试验中220例患者（n = 112接受奥希替尼治疗；n = 108接受安慰剂治疗）的探索性事后分析中，探讨了基于肿瘤信息的、循环肿瘤DNA检测的分子残留病（MRD）是否能够预测复发。在本研究中，MRD比影像学DFS事件提前出现的中位时间为4.7个月（95%置信区间，2.2 - 5.6个月）。奥希替尼组与安慰剂组患者36个月时的DFS和无MRD事件率分别为86%和36%（风险比，0.23（95%置信区间，0.15 - 0.36））。在奥希替尼组中，28例（25%）患者检测到DFS或MRD事件；大多数事件发生在奥希替尼停药后（28例中的19例，68%）以及停止奥希替尼治疗后的12个月内（19例中的11例，58%）。奥希替尼治疗24个月时，DFS和无MRD事件率为66%。在本研究中，双臂的大多数患者中MRD比DFS事件出现得更早。在辅助奥希替尼治疗及治疗后随访期间，大多数患者维持DFS和无MRD事件状态，大多数MRD或DFS事件发生在奥希替尼治疗中断或完成后。MRD检测可能潜在地识别出可能从更长时间的奥希替尼辅助治疗中获益的患者，尽管这需要临床确认。ClinicalTrials.gov标识符：NCT02511106 。
