Senior Department of Oncology, the Fifth Medical Center of PLA General Hospital, Beijing, China.
Thorac Cancer. 2023 Jul;14(20):1980-1990. doi: 10.1111/1759-7714.14980. Epub 2023 Jun 2.
To dynamically monitor the changes of genomic characteristics during lorlatinib treatment and analyze the resistance profile of lorlatinib in ALK-positive advanced Chinese patients with non-small cell lung cancer (NSCLC) with first- and second-generation ALK inhibitor resistance.
Ten eligible patients who were from a phase 2 study in China and admitted to the Fifth Medical Center of PLA General Hospital were analyzed. Blood samples were collected for next-generation sequencing (NGS) to characterize genetic variation at baseline, during treatment, and after disease progression.
Among the 10 patients treated with lorlatinib, objective response rate (ORR) was 50%. The median progression-free survival (PFS) was 13.3 months, and median overall survival (OS) was 15.6 months. At baseline, the mutation frequency of ALK in circulating tumor DNA (ctDNA) was higher in the group who received two lines of previous anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), and a similar trend was observed for TP53. After one follow-up cycle, the decreased variant allele frequency (VAF) had a trend to be predictive for responses. In six patients in which blood samples had been taken after lorlatinib resistance, ALK compound mutations were found in three patients (50%), which were G1202R/L1196M, L1196M/D1203N, and G1202R/F1174C. The DNMT3A N403Tfs*4, ERCC3 E259D, and GNAS p.A436_P459del variants were only detected after progression in two of the other three patients without ALK compound mutations.
The dynamic changes of genomic characteristics during lorlatinib treatment revealed the mutation landscape of Chinese patients with NSCLC after ALK-TKI resistance, indicated that the resistance profile of lorlatinib were heterogeneous, which laid the foundation for subsequent treatment to overcome lorlatinib resistance.
为了动态监测 lorlatinib 治疗过程中基因组特征的变化，并分析第一代和第二代 ALK 抑制剂耐药的 ALK 阳性晚期中国非小细胞肺癌（NSCLC）患者对 lorlatinib 的耐药谱。
对来自中国的 2 期研究并入住解放军总医院第五医学中心的 10 名符合条件的患者进行分析。采集血样进行下一代测序（NGS），以在基线、治疗期间和疾病进展后描述遗传变异。
在接受 lorlatinib 治疗的 10 名患者中，客观缓解率（ORR）为 50%。中位无进展生存期（PFS）为 13.3 个月，中位总生存期（OS）为 15.6 个月。在基线时，循环肿瘤 DNA（ctDNA）中 ALK 的突变频率在接受两种以前的间变性淋巴瘤激酶-酪氨酸激酶抑制剂（ALK-TKIs）的患者中更高，TP53 也有类似的趋势。在一个随访周期后，降低的变异等位基因频率（VAF）有预测反应的趋势。在 lorlatinib 耐药后采集血样的 6 名患者中，发现了 3 名患者（50%）的 ALK 复合突变，分别为 G1202R/L1196M、L1196M/D1203N 和 G1202R/F1174C。在另外 3 名没有 ALK 复合突变的患者中，只有在进展后才检测到 2 名患者的 DNMT3A N403Tfs*4、ERCC3 E259D 和 GNAS p.A436_P459del 变异。
lorlatinib 治疗过程中基因组特征的动态变化揭示了中国 NSCLC 患者在 ALK-TKI 耐药后的突变景观，表明 lorlatinib 的耐药谱具有异质性，为克服 lorlatinib 耐药的后续治疗奠定了基础。
