Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, Turin, Italy -
Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, Turin, Italy.
Minerva Med. 2022 Apr;113(2):315-332. doi: 10.23736/S0026-4806.21.07693-X.
The treatment landscape of advanced non-small cell lung cancer (NSCLC) patients has dramatically changed over the past 10 years, particularly thanks to the advent and development of several tyrosine kinase inhibitors (TKI) targeting oncogenic drivers. Among them, patients bearing anaplastic lymphoma kinase (ALK) translocations, which are causative of 3-5% of all advanced NSCLC, have seen dramatically improved their clinical outcomes moving life expectancy at 5 years from less than 5% to 50%. In fact, multiple ALK inhibitors (ALKi) entered in the therapeutic algorithm of ALK+ patients, multiplying their treatment opportunities. Remarkably, in the near future we could take advantage of up to different 6 molecules for the first-line approach (crizotinib, ceritinib, alectinib, brigatinib, plus ensartinib and lorlatinib). Among available ALKi, brigatinib, a second-generation (2G) inhibitor, showed notable activity in this setting, also against central nervous system (CNS) disease, and a good safety profile, supporting its approval as upfront treatment based on the ALTA-1L trial results. With a peculiar profile of enzymatic targets, brigatinib represents a valuable opportunity in the ALK targeting journey, albeit having to balance its safety profile. The abundance of therapeutic options for these patients poses nontrivial questions; in absence of direct comparisons of efficacy is not easy to define the best approach and, more compelling, the correct administration sequence in order to give the best therapeutic chances to ALK+ lung cancer patients. In such wide variety of options, we reviewed the preclinical and clinical efficacy data of brigatinib, its pharmacological and safety profile, like also actual and potential future applications in the ALK+ NSCLC scenario. Through a spurious exercise of an indirect comparison with other available 2G ALKi, we tent to summarize the required knowledge to properly choose the best drug at the right time. Furthermore, we reviewed available data on molecular resistance mechanisms and putative therapeutic applications in other contexts, such as ROS1+ NSCLC patients or EGFR+ ones progressing to osimertinib.
在过去的 10 年中，晚期非小细胞肺癌（NSCLC）患者的治疗格局发生了巨大变化，特别是由于几种针对致癌驱动因素的酪氨酸激酶抑制剂（TKI）的出现和发展。其中，患有间变性淋巴瘤激酶（ALK）易位的患者，占所有晚期 NSCLC 的 3-5%，其临床结局得到了显著改善，5 年生存率从不到 5%提高到 50%。事实上，多种 ALK 抑制剂（ALKi）进入了 ALK+患者的治疗方案，增加了他们的治疗机会。值得注意的是，在不久的将来，我们可以利用多达 6 种不同的分子作为一线治疗方法（克唑替尼、塞瑞替尼、阿来替尼、布加替尼、恩沙替尼和劳拉替尼）。在现有的 ALKi 中，第二代（2G）抑制剂布加替尼在这一治疗环境中表现出显著的活性，对中枢神经系统（CNS）疾病也有良好的疗效，且安全性良好，支持其根据 ALTA-1L 试验结果作为一线治疗药物获得批准。布加替尼具有独特的酶靶点谱，是 ALK 靶向治疗中的一个有价值的选择，尽管需要平衡其安全性。这些患者的治疗选择很多，由于缺乏疗效的直接比较，因此很难确定最佳治疗方法，更有说服力的是，为了给 ALK+肺癌患者提供最佳的治疗机会，确定正确的治疗顺序。在如此多的选择中，我们回顾了布加替尼的临床前和临床疗效数据、药理学和安全性概况，以及其在 ALK+NSCLC 中的实际和潜在的未来应用。通过与其他可用的 2G ALKi 进行间接比较的假设性练习，我们试图总结出在正确的时间选择最佳药物所需的知识。此外，我们还回顾了关于分子耐药机制和在其他情况下（如 ROS1+ NSCLC 患者或进展为奥希替尼的 EGFR+患者）的潜在治疗应用的可用数据。
