Reference Detail

Ref Type

Journal Article

PMID

(38961982)

Authors

He Q, Yu X, Yan J, Shi X, Pan H

Title

Changing ALK-TKI mechanisms of resistance in re-biopsies of ALK-rearranged NSCLC: ALK mutations followed by SCLC-like histologic transformation: A case report.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Heliyon	10	11	2024 Jun 15	e32030	Heliyon

URL

Abstract Text

Anaplastic lymphoma kinase (ALK) inhibitors are the recommended treatment of ALK-rearranged non-small cell lung cancer but are prone to eventual drug resistance. Herein we report a 45-year-old Asian woman diagnosed with EML4-ALK rearranged lung adenocarcinoma. Small cell lung cancer-like phenotypic transformation occurred when resistance to crizotinib treatment. Next-generation sequencing was performed and detected an ALK rearrangement co-existent with a TP53 gene mutation in the small cell specimens. The patient had a good response to alectinib with a progression-free survival >7 months. After disease progression, newly emerged ALK p.G1269A and p.L1196 M gene mutations co-existent with ALK rearrangement were detected. The patient had a good initial response to ceritinib treatment, which last for >12 months. After ceritinib failure, however, more complicated mutations within the ALK kinase domain (p.G1269A, p.L1196 M, newly emerged p.D1203 N, and p.L1122V) were detected. Ultimately, due to terminal rapid progression and resistance to lorlatinib, the overall survival was nearly 3 years. Our case showed that next-generation ALK-tyrosine kinase inhibitors (TKIs) may be an appropriate choice after transformation to small cell lung cancer and failure to one ALK-TKI. Sequential biopsies and gene mutation monitoring are important to arrange the sequence of different generation ALK-TKIs. Appropriate sequential therapies may yield a prolonged response with a satisfactory quality of life in patients with advanced ALK-rearranged non-small cell lung cancer.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK L1196M ALK G1269A	lung adenocarcinoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK L1196M and G1269A were identified in post-progression lymph node biopsy with a poorly differentiated adenocarcinoma pathology in a patient with metastatic lung adenocarcinoma and transformed small cell carcinoma harboring EML4-ALK, who previously achieved a partial response on Alecensa (alectinib) treatment (PMID: 38961982).	38961982
EML4 - ALK ALK L1122V ALK L1196M ALK D1203N ALK G1269A	lung adenocarcinoma	predicted - resistant	Ceritinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK D1203N and L1122V were identified in post-progression biopsy in a patient with metastatic lung adenocarcinoma harboring EML4-ALK, ALK G1269A, and ALK L1196M, who previously achieved a partial response on Zykadia (ceritinib) treatment (PMID: 38961982).	38961982
EML4 - ALK ALK L1196M ALK G1269A	lung adenocarcinoma	predicted - sensitive	Ceritinib	Case Reports/Case Series	Actionable	In a clinical case study, fifth-line Zykadia (ceritinib) treatment resulted in a partial response with a progression-free survival of approximately 5 months in a patient with metastatic poorly differentiated lung adenocarcinoma harboring EML4-ALK, ALK G1269A, and ALK L1196M (PMID: 38961982).	38961982