What Is ALK-Positive Lung Cancer?

ALK-positive lung cancer is a type of non-small cell lung cancer (NSCLC) in which the cancer cells have a mutation in the anaplastic lymphoma kinase (ALK) gene. The mutation is a gene rearrangement: an abnormal fusion of ALK and another gene, echinoderm microtubule-associated protein-like 4 (EML4).

This fusion causes cell enzymes (specialized proteins) to send signals to mutated cancer cells instructing them to divide and multiply more quickly than usual. The result: the spread of lung cancer.

As with other types of lung cancer linked to genetic mutations, ALK rearrangement can be treated with targeted therapy drugs, allowing you to manage your cancer. This has led to better survival rates among patients who have stage 4 lung cancer.

ALK-Positive Lung Cancer Symptoms

The ALK mutation is, by far, most common in people with lung adenocarcinoma, a type of NSCLC.

This type of cancer usually begins near the outer portion of the lungs away from the airways. Symptoms often don't begin until the cancer has spread toward the center of the lungs. When symptoms do appear, they usually manifest with a chronic cough and bloody sputum.

Young women and nonsmokers, who may never suspect that they have cancer, can develop ALK mutations. It is very common for this type of cancer to be missed until it is at an advanced stage.

Causes

The ALK rearrangement is present in 3% to 5% percent of people with NSCLC. That may sound like a small number but considering the number of people diagnosed with lung cancer annually, it means that there are around 10,000 newly diagnosed cases of ALK-positive disease each year in the United States.

The types of mutations present in lung cancers vary depending upon the type of lung cancer. The ALK mutation is most common in people with lung adenocarcinoma, but in rare cases ALK lung cancer has been found in squamous cell carcinoma of the lungs (another type of NSCLC) and small cell lung cancer.

This fusion gene isn’t a hereditary mutation like the BRCA mutations which are found in some people with breast and other cancers. People who have lung cancer cells positive for the EML4-ALK fusion gene weren’t born with cells that had this mutation and didn’t inherit a tendency to have this mutation from their parents.

Instead, this is an acquired mutation that develops in some cells due to a variety of factors. For instance, exposure to environmental carcinogens may damage genes and chromosomes and result in mutated cells.

In addition, the EML4-ALK fusion gene is not exclusively related to lung cancer. It may also be found in neuroblastoma and anaplastic large cell lymphoma.

Risk Factors

Certain people are more likely to have cancer cells with the ALK fusion gene:

• Younger patients (55 years and under)
• People who have never smoked (or smoked very little)
• Women
• People of East Asian ethnicity

In studies, NSCLC patients younger than 40 tested positive for the EML4-ALK fusion gene 34% of the time compared to about 5% of people of all ages with NSCLC.

Diagnosis

An ALK rearrangement is diagnosed through genetic testing (also known as molecular profiling). Healthcare providers obtain a sample of a lung tumor via a tissue biopsy or may examine a blood sample obtained via a liquid biopsy. These samples are checked for biomarkers that show the ALK mutation is present.

A few other tests that suggest an ALK mutation may be present include:

• Bloodwork: Anyone with metastatic adenocarcinoma of the lung will be checked for common mutations (eg EGFR, ALK, ROS1).
• Radiology: Imaging of ALK-positive lung cancer can appear different from other types of NSCLCs, which may help direct testing for the mutation early.

Treatment

ALK-positive lung cancer is treated with oral drugs that work to shrink advanced lung cancer tumors.

The drugs that have been approved by the U.S. Food and Drug Administration (FDA) to target ALK-positive lung cancer are called ALK inhibitors and include:

• Alecensa (alectinib)
• Alunbrig (brigatinib)
• Lorbrena (lorlatinib)
• Xalkori (crizotinib) 
• Zykadia (ceritinib)

If you've tested positive for the ALK gene rearrangement, ALK inhibitors are usually used instead of chemotherapy as the first course of treatment. In some cases, healthcare providers may recommend starting with chemo treatment and begin ALK medications only after the therapy has stopped working.

How ALK Inhibitors Work

Tyrosine kinases are cell proteins that allow signals to be sent from one cell to another. Tyrosine kinase receptors located on the cells receive these signals.

To understand how ALK-targeted therapy medications work, think of the cell's tyrosine kinase protein as a messenger that sends a message understood only by the tyrosine kinase receptor. If you have an ALK mutation, signals are sent to the cell's growth center telling cancer cells to divide without stopping.

Kinase inhibitor medications work by blocking the receptor. As a result, the abnormal signal telling the cancer cells to divide and grow never gets communicated.

It’s important to keep in mind that tyrosine kinase inhibitors are not a cure for lung cancer, but rather a treatment that allows a tumor to be kept in check.

Tumors can be managed for years with these drugs, reducing the likelihood that the cancer cells will spread.

Resistance

Lung cancers may initially respond very well to targeted therapy medications. However, patients almost always become resistant to the medication over time.

If you develop resistance to an ALK inhibitor, your healthcare provider will try a new medication or a combination of medications. New medications continue to be studied in clinical trials for people who develop resistance.

Medications may also need to be adjusted because cancers can further mutate over time.

For instance, Lorbrena (lorlatinib), which is approved as a first-line therapy, is also approved for people previously treated with other ALK inhibitors. It is an ALK inhibitor used to treat some of the secondary mutations that make cancers resistant to other ALK drugs. It was found to be effective in roughly half of the people who had become resistant to other drugs in this class. The median duration of action was 12.5 months.

Treatment Side Effects

Like other cancer medications, ALK inhibitors have side effects. These should be mild compared to the side effects of chemotherapy, but they still may be uncomfortable and disrupt everyday life.

Common adverse reactions to Xalkori (crizotinib) include:

• Vision disorders
• Nausea
• Diarrhea
• Vomiting
• Edema
• Constipation
• Elevated transaminases (related to liver damage)
• Fatigue
• Decreased appetite
• Upper respiratory infection
• Dizziness
• Neuropathy

Another rare but severe side effect is interstitial lung disease, which can be fatal.

Cost

The newer medications that target cancer cell abnormalities like ALK mutations often come with a steep price tag, but there are options available.

For those who don’t have insurance, there are government as well as private programs that can help. For those with insurance, copay assistance programs may help defray costs.

In some cases, the manufacturer of the drug may be able to supply medications at a reduced cost. And, importantly, you may be able to receive free treatment if you participate in a clinical trial.

Prognosis

While the overall five-year survival rate for NSCLC is about 25% and only 2 to 7% for advanced-stage lung cancer, researchers have found that the median survival for people with stage 4 ALK-positive lung cancer is 6.8 years with the right care. This survival rate held true even for those whose lung cancer had spread to the brain (brain metastases).

A study published in The New England Journal of Medicine found that treatment with Xalkori (crizotinib) results in a median progression-free survival of approximately 10 months. There is roughly a 50 to 60% response rate to the drug. This is a dramatic finding because the participants in the study had progression-free survival of around three months with chemotherapy.

While studies don't show increases in overall survival for all ALK rearrangement treatments, there is a clear improvement in the quality of life offered with these drugs and the possibility of living progression-free without serious side effects.

A Word From Verywell

If you have been diagnosed with cancer, discuss your options for genetic testing with your healthcare provider. A number of genetic tests are available and sometimes the results can help guide treatment. If possible, consider going to a cancer center that sees a high volume of lung cancer patients so you have access to the most advanced testing and treatment options, as well as possible experimental treatments to consider.