ALK Positive Lung Cancer Overview and Treatment

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ALK-positive lung cancer is a non-small cell lung cancer (NSCLC) that harbors a mutation in a gene called ALK (anaplastic lymphoma kinase). More precisely, it's a gene rearrangement—a fusion of two genes known as ALK and EML4 (echinoderm microtubule-associated protein-like 4). This abnormal fusion impacts cell enzymes (proteins) on the cancer cells. The enzymes, which act as chemical messengers, send signals to the mutated cancer cells telling them to divide and multiply more quickly than usual, and this creates a proliferation of cancerous cells.

As with other types of lung cancer related to genetic mutations, ALK rearrangement can now be treated fairly effectively with targeted therapy drugs, which allow you to manage your cancer. This has led to better survival rates among patients at all stages of lung cancer.

Causes

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

This fusion gene isn’t a hereditary mutation like the BRCA mutations in some people with breast cancer (and some other cancers). People who have a lung cancer 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.

The EML4-ALK fusion gene is not exclusively related to lung cancer. It may also be found in people with neuroblastoma and anaplastic large cell lymphoma.

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

Certain people are more likely to have the ALK fusion gene: Younger patients, people who have never smoked (or smoked very little), women, and those with 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). Doctors obtain a sample of a lung tumor via a tissue biopsy and may examine a blood sample obtained via a liquid biopsy. These samples are checked for biomarkers that show the mutation is present.

Researchers are also looking at ways to determine if an ALK mutation is present before genetic testing is done, or could substitute for genetic testing. A few things that suggest an ALK mutation may be present include:

  • Bloodwork: A test called CEA (carcinoembryonic antigen) tends to be negative or show low levels in people with ALK mutations.
  • Radiology: Image tests of ALK-positive lung cancer appear different than other types of NSCLCs, which may help doctors identify the mutations early.

Several organizations have worked together to develop guidelines on who should be tested for an ALK mutation. The consensus is that all patients with advanced-stage adenocarcinoma should be tested for ALK and other treatable genetic mutations, regardless of gender, smoking history, other risk factors, and race.

These guidelines are somewhat flexible. Doctors may recommend that other people undergo testing as well. For example, testing may be recommended for someone who has never smoked, even though their type of lung cancer does not appear to be adenocarcinoma.

Other doctors insist that everyone diagnosed with NSCLC undergo genetic testing.

Treatment

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

The drugs that have been approved by the FDA to target ALK positive lung cancer are called ALK inhibitors and include:

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

If you've tested positive for the ALK gene rearrangement, ALK inhibitors are usually used instead of chemotherapy as the first course of treatment. Although, doctors may sometimes start with chemo treatment and begin ALK medications only after chemo has stopped working.

How ALK Inhibitors Work

Tyrosine kinases are elements of cells that allow signals to be sent from one cell to another. Cells have tyrosine kinase receptors that receive these signals. To understand how ALK targeted therapy medications work, think of the cell's tyrosine kinase receptor as a lock and the tyrosine kinase protein (which holds the message) as a key. If you have an ALK mutation, you have an abnormal key. When the mutated key is “inserted,” signals are sent to the cell's growth center telling cancer cells to divide without stopping.

Medications such as Xalkori (crizotinib) work by blocking the keyhole—as if you filled in the keyhole with concrete. Thus, the signal telling the cancer cells to divide and grow never gets communicated.

Tumors can be managed for years with these drugs, ensuring that the cells do not spread.

Goal: Control Not Cure

It’s important to keep in mind that tyrosine kinase inhibitors are not a cure for lung cancer, but rather something that allows a tumor to be kept in check—much as a medication for diabetes may control the disease but does not cure it. It is hoped that in the future, lung cancer may be treated like other chronic diseases such as diabetes.

Resistance

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

Resistance may develop within nine weeks of beginning treatment, but for some people, medications can continue to be effective for many years

If you develop resistance to an ALK inhibitor, your doctor 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. Sometimes a medication that targets another treatable mutation (such as EGFR) may work even though a tumor was not initially positive for an EGFR mutation. For instance, the drug Lorbrena (loratinib) was approved for people previously treated with other ALK inhibitors and was found to be effective in roughly half of people who had become resistant to other drugs in this class. The median duration of action was 12.5 months

Components of vitamin E can significantly interfere with some ALK inhibitors. Talk with your doctor before taking vitamin E or any supplements while undergoing cancer treatment.

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 may 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 that has been noted is the development of interstitial lung disease, which can be fatal.

Prognosis

While the overall five-year survival rate for NSCLC is about 25%, which drops to two 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 their brain (brain metastases).

A study has also 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 people in the test had already failed to show progress on chemotherapy and had an expected response rate of 10% with a projected average progression-free survival of around 3 months.

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

The key to being able to take advantage of medications for ALK mutations is to undergo genetic mutations. While many doctors recommend that everyone with NSCLC be evaluated, many patients do not go through the testing. Discuss the option to test with your doctor. If possible, consider getting a second opinion at a cancer center that sees a large volume of lung cancer patients and may better support the decision to be tested.

Another concern is the cost. The newer medications that target abnormalities in cancer cells 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.

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