Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, ‘non-comparative’ assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile.
多种新一代ALK酪氨酸激酶抑制剂可作为ALK阳性非小细胞肺癌的一线治疗选择，其中阿来替尼与劳拉替尼是临床常用优选方案。然而，目前尚无两者间的直接对比研究，因此无法明确判定孰优孰劣。本研究对两项关键III期临床试验（ALEX研究与CROWN研究）进行了非比较性分析评估，这两项研究分别证实了阿来替尼与劳拉替尼相较于克唑替尼的优越性。总体而言，除脑转移病灶的筛选与评估标准存在差异外，两项研究在试验设计与患者特征方面高度相似。无论依据研究者评估还是盲态独立中心审查结果，劳拉替尼在无进展生存期风险比数值上均显示优势。值得注意的是，劳拉替尼的3年无进展生存率（64%）在数值上高于阿来替尼（46.4%）。尽管总体缓解率与颅内总体缓解率相近，但劳拉替尼的颅内完全缓解率更高：阿来替尼治疗组12个月中枢神经系统疾病进展累积发生风险为9.4%，而劳拉替尼组仅为2.8%。劳拉替尼的特异性毒性反应主要涉及血脂谱改变、外周性水肿及认知影响，但与克唑替尼相比未增加心血管风险，也未影响生活质量。此外，阿来替尼组因不良事件导致永久停药的比例（26%）在数值上高于劳拉替尼组（7%）。综上所述，尽管两种药物的总生存期数据尚未成熟，但劳拉替尼在保持可控毒性的同时，其疗效似乎优于阿来替尼。
肿瘤(癌症)患者之家