Tian Guangming, Zhao Xinliang, Nie Jun, Dai Ling, Hu Weiheng, Zhang Jie, Chen Xiaoling, Han Jindi, Ma Xiangjuan, Wu Di, Han Sen, Long Jieran, Wang Yang, Zhang Ziran, Fang Jian
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Oncology II, Peking University Cancer Hospital and Institute, Beijing, China.
Department of Medical Genetics, Peking University Health Science Center, Beijing, China.
J Thorac Dis. 2022 Jun;14(6):2201-2212. doi: 10.21037/jtd-22-622.
Anaplastic lymphoma kinase () gene rearrangement is a series of mutations of non-small cell lung cancer (NSCLC) patients. Since 2011, multiple ALK inhibitors (ALKis) have been developed and launched for targeted therapy. In this study, we sought to investigate different strategies of sequential applying the ALKis and their clinical benefits to the overall survival (OS).
A total of 176 patients with advanced NSCLC (stage IIIB-IV) harboring the rearrangement were included in this cohort study. They were diagnosed between February 1, 2012 and November 19, 2019 at Peking University Cancer Hospital. Clinical characters were reviewed from patients' records. Strategies of drugs, progression-free survival (PFS) and OS were collected during the follow-ups. The Kaplan-Meier method and multivariate Cox proportional-hazard analysis were used to conduct the analyses survival and to examine the relationship between the variables and OS.
A significantly longer OS was observed either in patients treated with crizotinib [N=106, median OS (mOS): 32.9 months] or in patients treated with a next-generation ALKi [N=34, mOS: not reached (NR)] as the initial ALKi, compared with patients treated with conventional chemotherapy but no ALKi (N=36, mOS: 10.3 months, P<0.001). After disease progression with initial crizotinib, patients who received no ALKi had shorter OS than those who received only crizotinib beyond progressive disease (CBPD) (mOS: 9.7 20.3 months; P=0.015), only subsequent next-generation ALKis (mOS: 9.7 41.1 months; P<0.001), and CBPD followed with subsequent next-generation ALKis (mOS: 9.7 months NR; P<0.001). Patients treated with 2 types of ALKi had better survival than those treated with 1 ALKi (mOS: 45.8 21.3 months, P=0.003), but no such survival benefit was observed in patients treated with ≥3 ALKis (P=0.366).
ALKis have been shown to be clinically effective in treating NSCLC patients with rearrangements. In the case of disease progression with crizotinib, either of CBPD or sequential other ALKis can extend patients' OS. The sequential application of multiple ALKis was found to be better than it of single ALKi in prolonging OS. However, the question of which inhibitor to select as the initial inhibitor needs to be examined further in future studies.
间变性淋巴瘤激酶（ALK）基因重排是非小细胞肺癌（NSCLC）患者的一系列突变。自2011年以来，已开发并推出了多种ALK抑制剂（ALKis）用于靶向治疗。在本研究中，我们试图研究序贯应用ALKis的不同策略及其对总生存期（OS）的临床益处。
本队列研究共纳入176例携带ALK重排的晚期NSCLC（IIIB-IV期）患者。他们于2012年2月1日至2019年11月19日在北京大学肿瘤医院确诊。从患者记录中回顾临床特征。在随访期间收集药物策略、无进展生存期（PFS）和OS。采用Kaplan-Meier法和多变量Cox比例风险分析进行生存分析，并检验变量与OS之间的关系。
与接受传统化疗但未使用ALKi的患者（N = 36，中位OS[mOS]：10.3个月，P<0.001）相比，接受克唑替尼治疗的患者（N = 106，mOS：32.9个月）或接受下一代ALKi作为初始ALKi治疗的患者（N = 34，mOS：未达到[NR]）观察到显著更长的OS。在初始克唑替尼治疗疾病进展后，未接受ALKi治疗的患者的OS短于仅接受克唑替尼超过疾病进展期（CBPD）的患者（mOS：9.7对20.3个月；P = 0.015）、仅接受后续下一代ALKis的患者（mOS：9.7对41.1个月；P<0.001）以及CBPD后接受后续下一代ALKis的患者（mOS：9.7个月对NR；P<0.001）。接受2种ALKi治疗的患者比接受1种ALKi治疗的患者生存期更好（mOS：45.8对21.3个月，P = 0.003），但接受≥3种ALKis治疗的患者未观察到这种生存益处（P = 0.366）。
ALKis已被证明在治疗携带ALK重排的NSCLC患者中具有临床疗效。在克唑替尼治疗疾病进展的情况下，CBPD或序贯使用其他ALKis均可延长患者的OS。发现序贯应用多种ALKis在延长OS方面优于单一ALKi。然而，哪种抑制剂作为初始抑制剂的问题需要在未来研究中进一步探讨。
