EML4-ALK positive lung cancer
EML4-ALK positive lung cancer is a primary malignant lung tumor whose cells contain a characteristic abnormal configuration of DNA wherein the echinoderm microtubule-associated protein-like 4 (EML4) gene is fused to the anaplastic lymphoma kinase (ALK) gene. This abnormal gene fusion leads to the production of a protein (EML4-ALK) that appears, in many cases, to promote and maintain the malignant behavior of the cancer cells.
The transforming EML4-ALK fusion gene was first reported in non-small cell lung carcinoma (NSCLC) in 2007.
Most lung carcinomas containing the EML4-ALK gene fusion are adenocarcinomas.
Signs and symptoms
The signs and symptoms of this lung cancer variant seem to mimic those of the underlying major cell type.
Screening for ALK positive lung cancer is now a standard of care in the United States and Canada. Screening can be done with immunostaining or FISH.
Crizotinib is a targeted therapy (FDA approved in 2011), manufactured by Pfizer and marketed under the brand name Xalkori and Crizalk that targets the EML4/ALK fusion gene.
Ceritinib is a second generation targeted therapy (FDA approved in 2014), manufactured by Novartis and sold under the brand name Zykadia that also targets the EML4 fusion gene, but as a second generation drug it has a smaller molecule that allows superior penetration of the Blood Brain Barrier (BBB) over Crizotinib and is more capable of protecting the Central Nervous System (CNS).
Brigatinib a second generation targeted therapy (FDA approved in 2017), manufactured by Takeda and is marketed under the brand name Alunbrig.
Ensartinib is a second generation targeted therapy (trial drug X-396), manufactured by XCovery.
Lorlatinib is a third generation targeted therapy (awaiting FDA approval under trial drug PF-6463922), manufactured by Pfizer.
TPX-0005 is a new third generation targeted therapy drug trial.
Treatment with crizotinib achieves 60% response rate. However, crizotinib showed no improvement on overall survival compared to chemotherapy. This may be due to the fact that there was a 70% crossover rate to crizotinib in patients treated initially with chemotherapy. Also, patients who tested negative for EML4/ALK fusion had a response rate to crizotinib of up to 35%.
EML4-ALK gene fusions occur almost exclusively in carcinomas arising in non-smokers. About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene. 4–6% of lung adenocarcinomas involve the fusion gene.
EML4-ALK mutation rarely occurs in combination with K-RAS or EGFR mutations.
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- Japan becomes first country to approve Roche’s alectinib for people with a specific form of advanced lung cancer
- New Oral Therapy To Treat ALK-Positive Lung Cancer. Dec 2015
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- Kumar, V; Abbas AK; Aster JC (2013). "Chapter 5". Robbins Basic Pathology (9th ed.). Elsevier Saunders. p. 212. ISBN 978-1-4377-1781-5.
- Entrez Gene EML4 echinoderm microtubule associated protein like 4 Homo sapiens
- ALK Positive Lung Cancer Patient and Caregiver Support: https://www.alkpositive.org/
- UpToDate - Anaplastic Lymphoma Kinase