Reference Detail

Ref Type

PMID

(36093526)

Authors

Hu H, Dai H, Ding L

Title

Durable clinical response to ALK tyrosine kinase inhibitors in ALK-rearranged non-small cell lung cancer: a case report.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Translational cancer research	11	8	2022 Aug	2967-2972	Transl Cancer Res

URL

Abstract Text

Anaplastic lymphoma kinase (ALK) rearrangement is a key oncogenic driver promoting the expression of ALK protein in non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitors (TKIs) have significantly improved survival benefits. However, the emergence of drug resistance limits their clinical benefits.We herein report a patient benefited from the sequential use of ALK TKIs (crizotinib, brigatinib, and lorlatinib) based on liquid biopsy testing. A female patient with stage IIIB NSCLC had a progression after chemotherapy and sequential radiotherapy. DNA-based next-generation sequencing (NGS) assay was performed in bronchoscopic biopsy tissue sample, demonstrating EML4-ALK (E13:A20) rearrangement. Crizotinib was administered, and partial response (PR) was achieved with a progression-free survival (PFS) of 8 months. Brigatinib was used when NGS simultaneously identified the six mutations ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A, with the retention of EML4-ALK. The best overall response of brigatinib was a stable disease, and the PFS was 10 months. Lorlatinib was prescribed at brigatinib progression with five out of the six ALK mutations undetected. The patient took alectinib after lorlatinib resistance with ALK L1196M. The overall survival was four years.EML4-ALK rearrangement was detected after chemotherapy treatment in an NSCLC patient with a remarkable therapeutic response with ALK TKIs based on liquid biopsy testing. We also revealed crizotinib acquired resistance mediated by multiple mutations ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A, while five mutations were undetected after brigatinib treatment. ALK F1174C may be the resistant mutation of brigatinib.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	E1129V	missense	unknown	ALK E1129V lies within the protein kinase domain of the Alk protein (UniProt.org). E1129V has been identified in the scientific literature (PMID: 34890832, PMID: 36093526, PMID: 33161228), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Apr 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK E1129V ALK I1171T ALK F1174C ALK F1174L ALK F1174V ALK G1269A	lung adenocarcinoma	predicted - sensitive	Brigatinib	Case Reports/Case Series	Actionable	In a clinical case study, Alunbrig (brigatinib) treatment resulted in stable disease with a progression-free survival of 10 months in a patient with lung adenocarcinoma harboring EML4-ALK (e13:e20), ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A (PMID: 36093526).	36093526
EML4 - ALK ALK F1174C ALK L1196M	lung adenocarcinoma	predicted - resistant	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK L1196M was identified in the post-progression biopsy of a patient with lung adenocarcinoma harboring EML4-ALK (e13:e20) and ALK F1174C, who previously responded to Lorbrena (lorlatinib) treatment (PMID: 36093526).	36093526
EML4 - ALK	lung adenocarcinoma	predicted - sensitive	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, Xalkori (crizotinib) treatment resulted in a partial response in a patient with lung adenocarcinoma harboring EML4-ALK (e13:e20) (PMID: 36093526).	36093526
EML4 - ALK ALK F1174C	lung adenocarcinoma	predicted - sensitive	Lorlatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lorbrena (lorlatinib) treatment resulted in stable disease lasting 6 months in a patient with lung adenocarcinoma harboring EML4-ALK (e13:e20) and ALK F1174C, who previously progressed on Xalkori (crizotinib) and Alunbrig (brigatinib) (PMID: 36093526).	36093526
EML4 - ALK ALK E1129V ALK I1171T ALK F1174C ALK F1174L ALK F1174V ALK G1269A	lung adenocarcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A were identified in the post-progression biopsy of a patient with metastatic lung adenocarcinoma harboring EML4-ALK (e13:e20), who previously responded to Xalkori (crizotinib) treatment (PMID: 36093526).	36093526