An anaplastic lymphoma kinase (ALK) rearrangement is a fusion between two genes: ALK and, most commonly, echinoderm microtubule-associated protein-like 4 (EML4). (In fact, the ALK gene rarely fuses to other genes.) The fusion of these two genes produces an abnormal ALK protein that causes cancer cells to grow and spread.

About 5% of patients with NSCLC in Western populations have tumors with an ALK fusion. The fusion between ALK and EML4 is more common among younger patients (median age at diagnosis is 52 years); nonsmokers or light smokers; and those with lung adenocarcinoma. It has rarely been found in patients with squamous cell lung cancer.1

How is it diagnosed?

Lung cancer is diagnosed using a variety of tests, including imaging, lab tests, biopsies, and biomarker testing. In the United States, a variety of tests can be used to make a diagnosis of ALK-positive NSCLC, including FISH (fluorescence in situ hybridization), IHC (immunohistochemistry), and NGS (next-generation sequencing). NGS falls under the umbrella term of “comprehensive biomarker testing.” Comprehensive biomarker testing can help determine if your lung cancer has an underlying biomarker or “driver mutation” that might make it respond to certain targeted treatments. It is important to know this information because it will help guide you and your doctor to the most appropriate treatments for your particular type of lung cancer.

Treatment options

Currently, ALK-positive NSCLC responds best to targeted therapy with tyrosine kinase inhibitors (TKIs). There are currently five FDA-approved ALK TKIs:

  • Alectinib (Alecensa®):2 Approved for patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test
  • Brigatinib (Alunbrig®):3 Approved for adult patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test
  • Ceritinib (Zykadia®):4 Approved for patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test
  • Crizotinib (Xalkori®):5 Approved for patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test
  • Lorlatinib (Lorbrena®):6 Approved for adult patients with metastatic ALK-positive NSCLC, as detected by an FDA-approved test

Treatment side effects

Side effects of the ALK TKIs differ by drug and by patient.1-5

Some common side effects of ALK TKIs as a group include:

  • Nausea
  • Vomiting
  • Diarrhea
  • Constipation
  • Fatigue
  • Swelling of the hands or feet

Among the more serious but less common side effects of ALK TKIs as a group are:1-5

  • Liver problems
  • Pneumonitis
  • Abnormal heartbeats

In addition, crizotinib (Xalkori®) has unique vision-specific side effects. These include:5

  • Trouble looking at light
  • Blurred vision
  • Double vision
  • Seeing flashes of light
  • New or increased floaters 

Low testosterone is one source of fatigue in patients being treated with crizotinib (Xalkori®). This can also lead to sexual dysfunction and depression.7

Get tips on managing treatment-related side effects.

Treatment challenges

Unfortunately, many patients on ALK TKIs eventually develop drug resistance, meaning the drug stops working and their cancer progresses. Luckily, ALK-positive NSCLC has a number of FDA-approved drugs, and patients are often able to switch to a different drug once one stops working.

Many research efforts are underway to understand drug resistance and find ways to combat it. For example, researchers are looking at various drug combinations that may help delay or prevent resistance from happening.

Another challenge for ALK-positive NSCLC is that it does not seem to respond to immunotherapy drugs. Researchers are actively exploring ways to open up immunotherapy options to patients with biomarker-driven NSCLC, including efforts to develop an ALK vaccine.

Learn more about recent efforts to combat drug resistance and develop an ALK vaccine.

Questions to ask your doctor

  1. Did I receive comprehensive biomarker testing? If not, can I?
  2. Am I eligible for a clinical trial?
  3. Am I eligible for immunotherapy?

Updated August 10, 2021


References

  1. Solomon B, Lovly C.  Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer. In: Lilenbaum RC. ed., Uptodate. Waltham, MA: UpToDate, Inc.: 2021. https://www.uptodate.com/contents/anaplastic-lymphoma-kinase-alk-fusion-oncogene-positive-non-small-cell-lung-cancer/print. Updated February 10, 2021. Accessed February 18, 2021.
  2. Alecensa® (alectinib) capsules [package insert]. Genentech, Inc. South San Francisco, CA. http://www.gene.com/download/pdf/alecensa_prescribing.pdf. Revised January 2021. Accessed February 12, 2021.
  3. Alunbrig® (brigatinib) tablets [package insert]. ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceuticals Company. Cambridge, MA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208772s008lbl.pdf. Revised May 2020. Accessed November 16, 2020.
  4. Zykadia® (ceritinib) capsules [package insert]. Novartis. East Hanover, NJ. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205755s011lbl.pdf. Revised November 2017. Accessed November 16, 2020.
  5. Xalkori® (crizotinib) capsules [package insert]. Pfizer, Inc. New York, NY. http://labeling.pfizer.com/showlabeling.aspx?id=676. Revised January 2021. Accessed February 12, 2021.
  6. Lorbrena® (lorlatinib) tablets [package insert]. Pfizer, Inc. New York, NY. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210868s004lbl.pdf. Revised March 2021. Accessed March 11, 2021
  7. Crizotinib lowers testosterone in lung cancer patients. The Oncology Nurse website. https://www.theoncologynurse.com/ash-2017-itp?view=article&secid=11001:top-sec-11001artid=14887:top-14887. Posted April 27, 2020. Accessed November 16, 2020.