Fabbri Laura, Di Federico Alessandro, Astore Martina, Marchiori Virginia, Rejtano Agnese, Seminerio Renata, Gelsomino Francesco, De Giglio Andrea
Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy.
Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, 40138 Bologna, Italy.
Diagnostics (Basel). 2023 Dec 25;14(1):48. doi: 10.3390/diagnostics14010048.
Following the results of the CROWN phase III trial, the third-generation macrocyclic ALK inhibitor lorlatinib has been introduced as a salvage option after the failure of a first-line TKI in ALK-rearranged NSCLC, while its precise role in the therapeutic algorithm of ROS1 positive disease is still to be completely defined. The ability to overcome acquired resistance to prior generation TKIs (alectinib, brigatinib, ceritinib, and crizotinib) and the high intracranial activity in brain metastatic disease thanks to increased blood-brain barrier penetration are the reasons for the growing popularity and interest in this molecule. Nevertheless, the major vulnerability of this drug resides in a peculiar profile of related collateral events, with neurological impairment being the most conflicting and debated clinical issue. The cognitive safety concern, the susceptibility to heterogeneous resistance pathways, and the absence of a valid alternative in the second line are strongly jeopardizing a potential paradigm shift in this oncogene-addicted disease. So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses.
根据CROWN III期试验结果，第三代大环ALK抑制剂洛拉替尼已被引入，作为ALK重排非小细胞肺癌一线TKI治疗失败后的挽救治疗选择，而其在ROS1阳性疾病治疗方案中的确切作用仍有待完全明确。由于血脑屏障穿透性增强，洛拉替尼能够克服对前代TKI（阿来替尼、布加替尼、色瑞替尼和克唑替尼）的获得性耐药，并且在脑转移疾病中具有较高的颅内活性，这些都是该药物越来越受欢迎和受到关注的原因。然而，这种药物的主要弱点在于其相关附带事件的特殊情况，神经功能损害是最具争议和讨论的临床问题。对认知安全性的担忧、对异质性耐药途径的易感性以及二线治疗中缺乏有效的替代方案，都严重危及这种致癌基因成瘾性疾病潜在的治疗模式转变。因此，在开具洛拉替尼处方时，临床医生必须面对两个截然相反的特点：巨大的治疗潜力，没有其前代TKI的固有局限性；细胞毒性活性受到耐受性欠佳的威胁，以及不可避免地出现我们尚未妥善应对的耐药机制。在本文中，我们从这种有前景的药物的创新分子和生化特性到引人关注的未来发展，再到不忘其弱点，对逐步将其引入临床实践给出批判性观点。
