ABSTRACT

Acquired mutations in anaplastic lymphoma kinase (ALK) gene have been implicated as the major resistance mechanism to ALK inhibitors; however, information on the treatment options after acquiring novel ALK secondary mutations is limited. Herein, we report the efficacy of lorlatinib upon the detection of a novel ALK G1202L after progression on brigatinib. Our patient was a 30-year-old man with ALK-rearranged advanced lung adenocarcinoma. He had a partial clinical response to crizotinib lasting 11 months. Brigatinib was then administered for 12.8 months with stable disease as the best response. Sequencing at progression revealed the retention of EML4-ALK fusion and the emergence of a novel ALK G1202L mutation. With no standard treatment available, lorlatinib was administered, which achieved disease control for 9 months. Our report reveals the efficacy of lorlatinib in targeting ALK G1202L and can serve as an option for the clinical management of patients with ALK-rearranged lung adenocarcinoma after acquiring G1202L-mediated resistance from prior ALK inhibitor therapy. Furthermore, we also demonstrate the sequential use of crizotinib, brigatinib, and lorlatinib in a patient with advanced ALK-rearranged lung adenocarcinoma with an overall progression-free survival of 33.3 months for the sequential ALK inhibitor regimens. His overall survival was 41.5 months inclusive of all regimens.

摘要

间变性淋巴瘤激酶 ( ALK ) 基因的获得性突变被认为是对 ALK 抑制剂的主要耐药机制；然而，关于获得新的ALK继发突变后治疗方案的信息是有限的。在此，我们报告了劳拉替尼在布加替尼治疗进展后检测到新型ALK G1202L 的疗效。我们的患者是一名 30 岁男性，患有ALK重排晚期肺腺癌。他对克唑替尼的部分临床反应持续了 11 个月。布加替尼随后给药 12.8 个月，疾病稳定作为最佳反应。进展测序揭示了EML4-ALK融合的保留和新型ALK 的出现G1202L 突变。在没有标准治疗的情况下，服用了劳拉替尼，达到了 9 个月的疾病控制。我们的报告揭示了劳拉替尼在靶向ALK G1202L 方面的功效，并且可以作为ALK重排肺腺癌患者在先前 ALK 抑制剂治疗中获得 G1202L 介导的耐药性后临床管理的一种选择。此外，我们还证明了克唑替尼、布加替尼和劳拉替尼在晚期ALK重排肺腺癌患者中的连续使用，序贯 ALK 抑制剂方案的总无进展生存期为 33.3 个月。他的总生存期为 41.5 个月，包括所有方案。