Stage IV Lung Cancer With ALK (Anaplastic Lymphoma Kinase) Rearrangement

Targeted therapy, one of the foundations of precision medicine, is a concept in the treatment of cancers that involves administering drugs that specifically target a known abnormality of the tumor cells that drives the growth of these cells. In contrast, most standard chemotherapy drugs target all actively dividing cells rather than just the cancer cells. Targeted therapies are sometimes called "molecularly targeted therapies" because they are developed to attack cancer cells with specific molecular changes. The choice to "target" specific genetic mutations or changes with drugs is made because these unfortunate genetic changes allow cancer cells to grow and survive.

Non-small cell lung cancers (NSCLC) have been shown over the past several years to contain so-called "driver" mutations in certain oncogenes. When these mutations are present, an abnormal protein is produced that leads to growth signaling changes that allow the tumor cells to grow and divide. Driver mutations or genetic changes have been identified in a number of different genes, including AKT1, ALK, BRAF, EGFR, HER2, KRAS, MEK1, MET, NRAS, PIK3CA, RET, and ROS1.

What is an ALK rearrangement?

The anaplastic lymphoma kinase (ALK) gene codes for a protein that is important for cell growth and division. In some lung cancers of the non-small cell type (NSCLC), there is a genetic abnormality known as translocation (in which a portion of a gene is moved to a different gene) of the ALK gene. This leads to the formation of an abnormal ALK fusion gene termed EML4-ALK. Screening for this fusion gene in NSCLC is important because "ALK-positive" tumors are highly sensitive to therapy with ALK-targeted inhibitor drugs.

How common are ALK rearrangements?

ALK rearrangements are found in about 3%-7% of lung cancers. ALK rearrangements are more likely to occur in certain tumors that form a glandular appearance when viewed microscopically (signet ring or acinar adenocarcinomas), in light smokers (<10 pack-years) or never-smokers, and in younger people. Diagnosis of the ALK rearrangement or the presence of other driver mutations is done on laboratory studies of tumor tissue.

What is metastatic lung cancer?

A metastatic, or stage IV, lung cancer is one that has spread beyond the lungs to other sites in the body. Some cancers are first diagnosed in stage IV when they have spread to other sites in the body.

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What medications are used in the treatment of stage IV lung cancer with ALK rearrangment?

Identification of an ALK gene rearrangement in a lung cancer is important for deciding the optimal treatment course. The ALK rearrangement means that drugs that specifically act against the abnormal fusion protein can be used. Three drugs, crizotinib (Xalkori), ceritinib (Zykadia), and alectinib (Alecensa), have been developed to target the activity of the abnormal fusion protein, and additional agents are under development. For patients with advanced or metastatic ALK-positive NSCLC who do not have metastases to the brain, the ALK inhibitor crizotinib is the recommended therapy. Ceritinib or alectinib is typically given if the cancer becomes resistant to crizotinib or if the patient is unable to tolerate crizotinib.

The era of molecularly targeted therapies for cancer represents an exciting and relatively recent development in the area of cancer research that allows doctors to administer drugs that specifically target tumor cells rather than all dividing cells. A number of drugs haven been developed to target genetic changes in specific cancers; a list of available targeted therapies can be found at the National Cancer Institute web site (http://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet). Even more drugs are in various stages of development and may be available in clinical trials. You can find more information about experimental targeted therapies at the link above or at the clinicaltrials.gov web site (https://clinicaltrials.gov).