背景:在第二代ALK酪氨酸激酶抑制剂(ALK-TKIs)的时代,关于进展模式的数据很少,抗性机制,以及随后的ALK阳性(ALK)非小细胞肺癌(NSCLC)的治疗方法。
方法:回顾性选择本中心的晚期ALK+NSCLC患者。队列1包括接受一线阿来替尼治疗后出现疾病进展的患者(n=20),而队列2包括接受克唑替尼和第二代ALK-TKIs序贯治疗后进展的患者(n=53).寡核苷酸进展定义为在不超过三个病变中发生疾病进展。当患者在放射学进展期间出现新症状或经历先前存在的症状恶化时,确定症状进展。
结果:与接受克唑替尼治疗的患者相比,第1组的中枢神经系统(CNS)进展和症状性CNS进展的发生率明显较低,比率为15.0%与56.6%(p=0.002)和5.0%与32.1%(p=0.016),分别。共有60.3%(44/73)的患者在第二代ALK-TKI耐药后进行了重复活检和下一代测序,ALK激酶结构域的二次突变成为耐药的主要机制(56.8%)。局部治疗应用于50%的寡进展病例。随后的ALK-TKIs证明无进展生存期(PFS)显着延长(8.6mvs.2.7米,p=0.021,HR=0.43,95CI:0.15-0.85)和长期总生存率(OS)(NA与11.9米,p=0.132,HR=0.50,95CI:0.18-1.25)在具有ALK抗性突变的患者中,与没有这种突变的人相比。对于第二代ALK-TKIs进展后无ALK耐药突变的患者,后续化疗或替代ALK-TKI治疗之间的生存结局无统计学显著差异.
结论:一线阿来替尼在保护中枢神经系统方面表现出优于克唑替尼的疗效。对于第二代ALK-TKIs耐药后出现ALK耐药突变的患者,应给予适当的敏感ALK-TKI;对于那些没有这种突变的人,化疗或第三代ALK-TKI的选择应基于患者的总体身体健康和个人偏好.
BACKGROUND: In the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and subsequent therapeutic approaches for ALK-positive (ALK+) non-small cell lung cancer (NSCLC).
METHODS: Patients with advanced ALK+ NSCLC were retrospectively selected from our center. Cohort 1 consisted of patients who experienced disease progression after receiving first-line alectinib treatment (n = 20), while Cohort 2 included patients who progressed following sequential treatment with crizotinib and second-generation ALK-TKIs (n = 53). Oligo-progression was defined as the occurrence of disease progression in no more than three lesions. Symptomatic progression was determined when patients developed new symptoms or experienced worsening of pre-existing symptoms during radiological progression.
RESULTS: The incidence of central nervous system (CNS) progression and symptomatic CNS progression was significantly lower in Cohort 1 compared to patients treated with crizotinib, with rates of 15.0% vs. 56.6% (p = 0.002) and 5.0% vs. 32.1% (p = 0.016), respectively. A total of 60.3% (44/73) patients underwent repeated biopsy and next-generation sequencing subsequent to the second-generation ALK-TKI
resistance, with secondary mutation in ALK kinase domain emerging as the predominant mechanism of
resistance (56.8%). Local therapy was applied to 50% of oligo-progression cases. Subsequent ALK-TKIs demonstrated significantly prolonged progression-free survival (PFS) (8.6 m vs. 2.7 m, p = 0.021, HR = 0.43, 95%CI: 0.15-0.85) and long-term overall survival (OS) (NA vs. 11.9 m, p = 0.132, HR = 0.50, 95%CI: 0.18-1.25) in patients harboring ALK
resistance mutations, compared to those without such mutations. For patients without ALK-resistant mutations following progression on second-generation ALK-TKIs, there was no statistically significant difference in survival outcomes between subsequent chemotherapy or alternative ALK-TKI treatments.
CONCLUSIONS: First-line alectinib demonstrated superior efficacy in protecting the CNS compared to crizotinib. For patients with ALK-resistant mutations following the
resistance to second-generation ALK-TKIs, appropriate sensitive ALK-TKI should be administered; for those without such mutations, the selection of chemotherapy or third-generation ALK-TKI should be based on the patient\'s overall physical health and personal preferences.