1 Massachusetts General Hospital, Boston, MA.
2 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
J Clin Oncol. 2019 Jun 1;37(16):1370-1379. doi: 10.1200/JCO.18.02236. Epub 2019 Mar 20.
Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non-small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that resistance mutations may represent a biomarker of response in previously treated patients.
Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for mutations using Guardant360. Tumor tissue DNA was analyzed using an mutation-focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to mutation status.
Approximately one quarter of patients had mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with mutations (62% 32% [plasma]; 69% 27% [tissue]). Progression-free survival was similar in patients with and without mutations on the basis of plasma genotyping (median, 7.3 months 5.5 months; hazard ratio, 0.81) but significantly longer in patients with mutations identified by tissue genotyping (median, 11.0 months 5.4 months; hazard ratio, 0.47).
In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with mutations compared with patients without mutations. Tumor genotyping for mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.
洛拉替尼是一种有效的、可穿透血脑屏障的第三代间变性淋巴瘤激酶（ALK）/ROS1 酪氨酸激酶抑制剂（TKI），在晚期 ALK 阳性非小细胞肺癌中具有强大的临床活性，包括在先前接受 ALK TKI 治疗失败的患者中。洛拉替尼反应的分子决定因素尚未确定，但临床前数据表明，耐药突变可能是先前治疗患者反应的生物标志物。
从洛拉替尼注册 2 期研究的 198 名 ALK 阳性非小细胞肺癌患者中采集基线血浆和肿瘤组织样本。我们使用 Guardant360 分析了血浆 DNA 中的 突变。使用 突变特异性下一代测序检测肿瘤组织 DNA。根据 突变状态评估客观缓解率、缓解持续时间和无进展生存期。
大约四分之一的患者通过血浆或组织基因分型检测到 突变。在对克唑替尼耐药的患者中，使用血浆或组织基因分型，洛拉替尼在有和无 突变的患者中的疗效相当。相比之下，在接受过 1 种或多种第二代 ALK TKI 治疗失败的患者中，有 突变的患者客观缓解率更高（血浆：62%[32%]；组织：69%[27%]）。基于血浆基因分型，无 突变的患者与有 突变的患者的无进展生存期相似（中位：7.3 个月[5.5 个月]；风险比：0.81），但组织基因分型检测到 突变的患者无进展生存期显著更长（中位：11.0 个月[5.4 个月]；风险比：0.47）。
在接受过 1 种或多种第二代 ALK TKI 治疗失败的患者中，与无 突变的患者相比，洛拉替尼在有 突变的患者中疗效更大。在第二代 TKI 治疗失败后对 突变进行肿瘤基因分型，可能可以识别出更有可能从洛拉替尼中获益的患者。
