Urbanska Edyta Maria, Koffeldt Peter Rindom, Grauslund Morten, Melchior Linea Cecilie, Sørensen Jens Benn, Santoni-Rugiu Eric
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
Int J Mol Sci. 2025 Jun 21;26(13):5969. doi: 10.3390/ijms26135969.
Choosing the optimal first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase () rearrangements can be challenging in daily practice. Although clinical trials with next-generation ALK-tyrosine kinase inhibitors (TKIs) have played a key role in evaluating their efficacy and safety, which patients benefit from a specific ALK-TKI may still be questioned. The methodological inconsistencies in these trials, which led to the inclusion of different patient populations, appear to have been inadequately addressed. rearranged NSCLC is a heterogeneous disease, and co-existing molecular alterations may affect the outcome. The questions explored in these trials appear insufficient to support a personalized approach to the first-line treatment, while defining long-term responders and early progressors would be clinically useful. This narrative review presents several considerations from oncologists' and pathologists' perspectives. We propose defining favorable and unfavorable features, such as histology, type of fusion, co-existing molecular alterations, plasma circulating tumor DNA (ctDNA, performance status, and brain metastases, to help identify patients with lower and higher risk of progression. Consequently, the most potent ALK-TKI to date, Lorlatinib, may be considered as the first-line treatment for high-risk patients with unfavorable features, while sequencing of ALK-TKIs may be appropriate for low-risk patients with favorable features. Although ALK signal inhibition is critical in this disease, it may not be sufficient for clinical control due to de novo co-alterations. A more personalized approach to first-line therapy requires consideration of risk factors for each patient.
在日常实践中，为晚期间变性淋巴瘤激酶（ALK）重排的非小细胞肺癌（NSCLC）患者选择最佳一线治疗方案可能具有挑战性。尽管新一代ALK酪氨酸激酶抑制剂（TKIs）的临床试验在评估其疗效和安全性方面发挥了关键作用，但哪些患者能从特定的ALK-TKI中获益仍可能受到质疑。这些试验中方法上的不一致导致纳入了不同的患者群体，这一问题似乎尚未得到充分解决。ALK重排的NSCLC是一种异质性疾病，共存的分子改变可能会影响治疗结果。这些试验中探讨的问题似乎不足以支持一线治疗的个性化方法，而定义长期缓解者和早期进展者在临床上会很有用。这篇叙述性综述从肿瘤学家和病理学家的角度提出了几点考虑。我们建议定义有利和不利特征，如组织学、ALK融合类型、共存的分子改变、血浆循环肿瘤DNA（ctDNA）、体能状态和脑转移，以帮助识别进展风险较低和较高的患者。因此，对于具有不利特征的高危患者，可考虑将迄今为止最有效的ALK-TKI洛拉替尼作为一线治疗，而对于具有有利特征的低危患者，ALK-TKIs的序贯治疗可能是合适的。尽管ALK信号抑制在这种疾病中至关重要，但由于新发的共同改变，它可能不足以实现临床控制。一线治疗采用更个性化的方法需要考虑每个患者的风险因素。
