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.
Some studies suggest that the papillary adenocarcinoma and the signet ring cell adenocarcinomavariants are more likely to carry this fused gene than other histological variants.
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).
Alectinib another second generation targeted therapy and was approved (for this) by Japan in 2014and by US FDA in 2015. , manufactured by Genentec and marketed under the brand name Alecensa.
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. –6% of lung adenocarcinomas involve the fusion gene.About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene. 4
EML4-ALK mutation rarely occurs in combination with K-RAS or EGFR mutations.