Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC

Autor: Xiya Ma, Kun Zhang, Jing Xu, Hongjun Gao, Shaoxing Yang, Haifeng Qin, Hong Wang, Fang Gao, Xiaoqing Liu
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Thoracic Cancer, Vol 14, Iss 20, Pp 1980-1990 (2023)
Druh dokumentu: article
ISSN: 1759-7714
1759-7706
DOI: 10.1111/1759-7714.14980
Popis: Abstract Background 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. Methods 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. Results 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. Conclusions 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.
Databáze: Directory of Open Access Journals
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