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

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...

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Autores principales: Ma, Xiya, Zhang, Kun, Xu, Jing, Gao, Hongjun, Yang, Shaoxing, Qin, Haifeng, Wang, Hong, Gao, Fang, Liu, Xiaoqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons Australia, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344744/
https://www.ncbi.nlm.nih.gov/pubmed/37265111
http://dx.doi.org/10.1111/1759-7714.14980
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author Ma, Xiya
Zhang, Kun
Xu, Jing
Gao, Hongjun
Yang, Shaoxing
Qin, Haifeng
Wang, Hong
Gao, Fang
Liu, Xiaoqing
author_facet Ma, Xiya
Zhang, Kun
Xu, Jing
Gao, Hongjun
Yang, Shaoxing
Qin, Haifeng
Wang, Hong
Gao, Fang
Liu, Xiaoqing
author_sort Ma, Xiya
collection PubMed
description 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.
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spelling pubmed-103447442023-07-15 Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC Ma, Xiya Zhang, Kun Xu, Jing Gao, Hongjun Yang, Shaoxing Qin, Haifeng Wang, Hong Gao, Fang Liu, Xiaoqing Thorac Cancer Original Articles 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. John Wiley & Sons Australia, Ltd 2023-06-02 /pmc/articles/PMC10344744/ /pubmed/37265111 http://dx.doi.org/10.1111/1759-7714.14980 Text en © 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Ma, Xiya
Zhang, Kun
Xu, Jing
Gao, Hongjun
Yang, Shaoxing
Qin, Haifeng
Wang, Hong
Gao, Fang
Liu, Xiaoqing
Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC
title Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC
title_full Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC
title_fullStr Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC
title_full_unstemmed Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC
title_short Dynamic monitoring of circulating tumor DNA to analyze genetic characteristics and resistance profile of lorlatinib in ALK positive previously treated NSCLC
title_sort dynamic monitoring of circulating tumor dna to analyze genetic characteristics and resistance profile of lorlatinib in alk positive previously treated nsclc
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344744/
https://www.ncbi.nlm.nih.gov/pubmed/37265111
http://dx.doi.org/10.1111/1759-7714.14980
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