Dagogo-Jack Ibiayi, Kiedrowski Lesli A, Heist Rebecca S, Lin Jessica J, Meador Catherine B, Krueger Elizabeth A, Do Andrew, Peterson Jennifer, Sequist Lecia V, Gainor Justin F, Lennerz Jochen K, Digumarthy Subba R
Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
JTO Clin Res Rep. 2023 Jun 1;4(8):100534. doi: 10.1016/j.jtocrr.2023.100534. eCollection 2023 Aug.
amplification is a potentially actionable resistance mechanism in -rearranged (ALK+) lung cancer. Studies describing treatment outcomes of this molecular subgroup are lacking.
We assembled a cohort of patients with ALK+ lung cancer and acquired amplification (identified by tissue or plasma) who received regimens targeting both ALK and MET. Efficacy and safety were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 4.03, respectively.
A total of 12 patients were included in the series. amplification was detected after a median of 1.5 (range 1-5) lines of therapy. Four distinct regimens were implemented to address amplification: crizotinib (n = 2), lorlatinib plus crizotinib (n = 6), alectinib plus capmatinib (n = 3), and alectinib plus crizotinib (n = 1). Partial responses were observed in five (42%) of 12 patients, including patients who received crizotinib (n = one of two), lorlatinib plus crizotinib (n = three of six), and alectinib plus capmatinib (n = one of three). Primary progression was observed in four patients (33%). Grades 1 to 2 peripheral edema, occurring in seven (58%) patients, was found with both crizotinib and capmatinib. One patient required dose reduction of capmatinib plus alectinib for persistent grade 2 edema. Across the regimens, one patient discontinued therapy for toxicity, specifically neurocognitive toxicity from lorlatinib plus crizotinib. At progression on ALK+ MET therapy, potential resistance mechanisms included copy number changes and kinase domain mutations.
Combined ALK and MET inhibition is associated with moderate antitumor activity in patients with ALK+ NSCLC with concurrent amplification. Prospective studies are indicated to confirm activity and identify individuals most likely to benefit from the treatment.
扩增是间变性淋巴瘤激酶重排（ALK+）肺癌中一种可能具有可操作性的耐药机制。目前缺乏描述该分子亚组治疗结果的研究。
我们收集了一组ALK+肺癌且存在MET扩增（通过组织或血浆鉴定）的患者，这些患者接受了同时靶向ALK和MET的治疗方案。分别使用实体瘤疗效评价标准第1.1版和不良事件通用术语标准第4.03版评估疗效和安全性。
该系列共纳入12例患者。在接受中位数为1.5（范围1 - 5）线治疗后检测到MET扩增。实施了四种不同的治疗方案来应对MET扩增：克唑替尼（n = 2）、洛拉替尼加克唑替尼（n = 6）、阿来替尼加卡马替尼（n = 3）以及阿来替尼加克唑替尼（n = 1）。12例患者中有5例（42%）观察到部分缓解，包括接受克唑替尼治疗的患者（2例中的1例）、洛拉替尼加克唑替尼治疗的患者（6例中的3例）以及阿来替尼加卡马替尼治疗的患者（3例中的1例）。4例患者（33%）观察到疾病进展。7例（58%）患者出现1至2级外周水肿，克唑替尼和卡马替尼治疗时均有发生。1例患者因持续性2级水肿需要减少卡马替尼加阿来替尼的剂量。在所有治疗方案中，1例患者因毒性（具体为洛拉替尼加克唑替尼导致的神经认知毒性）停止治疗。在ALK+ MET治疗进展时，潜在的耐药机制包括MET拷贝数变化和MET激酶结构域突变。
联合抑制ALK和MET在ALK+非小细胞肺癌合并MET扩增患者中具有中等抗肿瘤活性。需要进行前瞻性研究以证实其活性并确定最可能从该治疗中获益的个体。
