Itchins Malinda, Liang Shirley, Brown Chris, Barnes Tristan, Marx Gavin, Chin Venessa, Kao Steven, Yip Po Yee, Mersiades Antony J, Nagrial Adnan, Bray Victoria, Peters Geoffrey, Parakh Sagun, Garg Kavita, Li Bob T, McKay Matthew, O'Byrne Kenneth, John Thomas, Gill Anthony J, Molloy Mark P, Solomon Benjamin J, Pavlakis Nick
Royal North Shore Hospital, St Leonards, Australia.
Northern Clinical School, University of Sydney, St Leonards, Australia.
JTO Clin Res Rep. 2024 Jul 8;5(9):100703. doi: 10.1016/j.jtocrr.2024.100703. eCollection 2024 Sep.
ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring.
The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma.
A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants.
ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.
ALK 阳性肺癌是一种分子特征多样的疾病。随着药物暴露、驱动选择压力和耐药途径的出现，疾病将会复发。基于动态循环肿瘤 DNA（ctDNA）监测来研究新的治疗策略具有令人信服的理论依据。
单臂试点研究 ALKTERNATE 调查了在对第二代 ALK 抑制剂耐药的个体中，将劳拉替尼与克唑替尼交替固定周期使用的情况。动态 ctDNA 探索了其与疾病反应和疾病复发的相关性，并定义了疾病耐药性。主要结局是治疗失败时间，这是一个综合了耐受性、可行性和疗效的指标。次要结局包括标准生存指标、毒性、药代动力学分析以及患者报告的结局。三级结局是组织和血浆的蛋白质基因组分析。
共招募了 15 名个体；3 名对劳拉替尼诱导出现原发性耐药。有 12 名参与者接受了交替治疗，这种方法显示出安全性、可行性和有效性。患者报告的结局在治疗期间得以维持或改善，毒性与先前报告一致。药代动力学指标与单臂药物经验相似。中位治疗失败时间为 10 个月；总生存期为 23 个月。ctDNA 谱表明，在试验诱导时存在预先存在的 TP53 突变的个体以及没有清晰或清除 ctDNA 的个体中，生存期较差。该研究定义了一个高度异质性的群体，其中大量 ALK 与非 ALK 耐药变体共存。
ALKTERNATE 研究揭示了在 ALK 阳性非小细胞肺癌中采用新型交替 ALK 抑制剂策略的可行性。结果支持对该方法进行进一步研究，并提出一种灵活的设计，根据实时血浆分析结果选择药物和交替时间框架。将这一概念应用于初治患者可能也会优化治疗效果。
