Bestvina Christine M, Kim Chul, Daaboul Nathalie
Department of Medicine, University of Chicago Medical Center, 5841 S Maryland Ave, MC 2115, Chicago, IL, 60637, USA.
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Adv Ther. 2025 May 22. doi: 10.1007/s12325-025-03195-7.
Non-small cell lung cancer (NSCLC) treatment has been revolutionized by the advent of targeted therapies for tumors harboring specific actionable alterations. Targeted agents are now approved for use in patients with advanced NSCLC with various drivers including ALK rearrangements, BRAF V600E mutations, EGFR mutations, ERBB2 mutations, KRAS G12C mutations, MET exon 14 skipping alterations, NTRK fusions, RET rearrangements, and ROS1 rearrangements. Importantly, the availability of these agents has raised the clinical question of how to optimally sequence their use alongside chemotherapy and/or immunotherapy strategies, which are indicated for broader populations. Key considerations include (i) evidence for better outcomes when first-line treatment is initiated following availability of molecular profiling data; (ii) the decreasing proportion of patients able to receive therapy in each successive treatment line; (iii) the efficacy of targeted agents demonstrated in either single-arm trials or head-to-head comparisons with chemotherapy and/or immunotherapy, as compared with evidence for poor or modest efficacy of immunotherapy in patients with tumors with actionable drivers; (iv) real-world data showing better outcomes of patients with tumors with actionable alterations who received targeted therapies compared with those who did not; (v) the generally favorable safety profile of targeted therapies, as well as the potential for increased toxicity when immunotherapy precedes certain targeted agents; and (vi) patient-centric factors including the greater ease of administration of oral targeted therapies over intravenous chemotherapy or immunotherapy strategies. In line with these considerations, guidelines typically recommend most targeted agents approved for first-line use as initial therapy over chemotherapy and/or immunotherapy. In this podcast, the authors discuss the current therapeutic landscape of NSCLC with actionable alterations and provide their perspectives on treatment algorithms, and how to optimally sequence therapies for patients with tumors harboring actionable alterations, using patient cases to illustrate key principles.
针对具有特定可操作改变的肿瘤的靶向治疗的出现，彻底改变了非小细胞肺癌（NSCLC）的治疗方式。目前，靶向药物已获批用于治疗晚期NSCLC患者，这些患者具有多种驱动因素，包括ALK重排、BRAF V600E突变、EGFR突变、ERBB2突变、KRAS G12C突变、MET外显子14跳跃改变、NTRK融合、RET重排和ROS1重排。重要的是，这些药物的出现引发了一个临床问题，即如何在化疗和/或免疫治疗策略（适用于更广泛人群）的基础上，最佳地安排它们的使用顺序。关键考虑因素包括：（i）在获得分子谱分析数据后开始一线治疗时，疗效更佳的证据；（ii）在每个连续治疗线中能够接受治疗的患者比例不断下降；（iii）与在具有可操作驱动因素的肿瘤患者中免疫治疗疗效不佳或中等的证据相比，靶向药物在单臂试验或与化疗和/或免疫治疗的头对头比较中所显示的疗效；（iv）真实世界数据显示，接受靶向治疗的具有可操作改变的肿瘤患者比未接受靶向治疗的患者预后更好；（v）靶向治疗总体上良好的安全性，以及在某些靶向药物之前进行免疫治疗时毒性增加的可能性；（vi）以患者为中心的因素，包括口服靶向治疗比静脉化疗或免疫治疗策略给药更方便。基于这些考虑，指南通常推荐大多数获批用于一线治疗的靶向药物作为初始治疗，优先于化疗和/或免疫治疗。在本播客中，作者讨论了具有可操作改变的NSCLC的当前治疗格局，并就治疗算法以及如何为具有可操作改变的肿瘤患者最佳地安排治疗顺序提供了他们的观点，并用患者病例来说明关键原则。
