About ALK

When you first learn you have lung cancer, it's easy to get overwhelmed by what that means. The terminology and depth of the science can be confusing.

This page is to explain some background about ALK lung cancer. The point is to simplify it enough to help people get a basic understanding of ALK without needing a class in microbiology. This summary is based on my best understanding but always insert caveats. Here's what I've been able to gather so far.

    Lung cancer comes in different types. The two main types are seen above:
    1. Small Cell Lung Cancer (dark blue)- about 15% of all lung cancer
    2. Non Small Cell Lung Cancer, NSCLC (everything else) - about 85% of all lung cancer
    NSCLC can be further subdivided into three main subtypes above, based on where they originated:
    1. Adenocarcinoma (lt blue) - arises from the cells that line the air sacs (alveoli) in the lungs
    2. Squamous Cell Lung Cancer (gray) - arises from the [squamous] cells that line the passages leading from the windpipe (trachea) to the lungs (bronchi)
    3. Large Cell Lung Cancer (green) - arises from the epithelial cells that line the lungs
    ALK Positive lung cancer is most commonly Adenocarcinoma NSCLC. Once in a while, ALK can occur with other types, including squamous cell or small cell lung cancer, but this is rare; ALK is usually an adenocarcinoma.

    Driver Mutations
     
    Lung cancer occurs when certain genes mutate and allow proteins to reproduce out of control.

    Adenocarcinoma NSCLC has many gene mutations which drive the huge growth that results in cancer. ALK+, ROS1, and EGFR are three of the most common and treatable mutations right now.

    Some of the other driver mutations we know about include KRAS, BRAF, HER2, MET, MEK, FGFRA, PIK3CA, and RET. Some of these currently have treatments, while others do not.

    More mutations are being identified all the time, and new drugs for them are in development or clinical trials now. This is truly an area of rapidly expanding treatment. This is why it is vital for ALL lung cancer patients to get genomic testing and keep on top of the latest research developments for their particular mutation.

    What is ALK?

    EML4-ALK Translocation Illustration
    The blue circles with dots at bottom are
    ALK results on FISH tests

    ALK stands for Anaplastic Lymphoma Kinase. The ALK gene produces a protein which helps regulate cell growth. Sometimes, this gene breaks and fuses with another gene out of its normal order. This allows tyrosine kinase proteins to be produced out of control, leading to cancer.

    The ALK rearrangement in NSCLC was discovered by Japanese researchers in August 2007. This was lucky timing because there was a medication (crizotinib) already in development for a related cancer (MET). Crizotinib was rushed into clinical trials where it had some amazing results in preliminary trials. This first targeted therapy for ALK was approved by the FDA in 2011.

    In the most common version of ALK, the ALK gene on chromosome 2p fuses to the echinoderm microtubule-associated protein-like 4 (EML4) gene. That's why a lot of research uses the term, "EML4-ALK Fusion Oncogene."

    Other common terms include "ALK rearrangement," "ALK Fusion," or "ALK translocation." They all mean basically the same thing.

     If that all sounds like Greek to you, you are not alone. Lots of people have difficulty understanding how different lung cancers develop. A simplified way to understand it is to picture two genes breaking apart and then being fused together in the wrong order. This causes the cells to grow out of control, creating cancer.


    Sometimes, the ALK gene fuses to genes other than EML-4, but most of the time the fusion is between EML4 and ALK. The ALK gene can also become oncogenic (driving cancer) by "gaining additional gene copies or with mutations of the actual DNA code for the gene itself."

    The cancer most associated with ALK fusions is lung cancer. However, when ALK fuses with other genes besides EML-4, it can also cause other forms of cancer like Inflammatory Myofibroblastic Tumor (IMT), neuroblastoma, or anaplastic large cell lymphoma.

    Who Gets ALK?

    People who get ALK+ lung cancer are usually never-smokers and younger than average. Average age for lung cancer on average is about 70; for ALK it's about 55 (some sources say 52). In other words, ALK+ tends to be a cancer of young and middle-aged non-smokers.

    This is borne out even more strongly if you look only at younger adults. Across the age spectrum, only 3 to 5 percent of NSCLC patients test positive for EML4-ALK. However, among never-smokers only who are younger than 40 years of age, about half will test positive for the EML4-ALK fusion gene.

    Of course there are always exceptions. Some smokers get ALK lung cancer, and some senior citizens get it too. Once in a while, even children and teens get ALK lung cancers. Therefore, ALL people who have NSCLC should be tested for genetic mutations, even if they don't fit the "typical" profile.

    Testing for genomic (tumor) mutations can be done in several ways. These include:
    • Fluorescence In Situ Hybridization (FISH) 
    • Immunohistochemistry (IHC) 
    • Next-Generation Sequencing (NGS) 
    FISH testing and IHC testing are the tests most commonly paid for by insurance for first-time testing. NGS is more expensive because it tests more things, so it is usually saved for once resistance develops.

    Liquid biopsies using blood or plasma are all the rage these days because they are simpler and less invasive than traditional tissue biopsies. However, while they rarely have a false positive (incorrectly identifying the presence of certain mutations), they often have false-negatives (tell you something is not there when it is). In other words, liquid biopsies are very good at telling you what you do have but they are not very accurate at telling you what you do not have.

    Initial testing usually takes a couple of weeks. If the patient's cancer is very far advanced and the person is quite ill, doctors may suggest starting chemotherapy while they wait for test results. However, most opt to wait for test results before starting a course of therapy in hopes of having a treatable mutation.

    Treatment for ALK


    Most cancer in the past was treated with I.V. chemotherapy. This was the nuclear option, carpet bombing and trashing everything in its path. It targeted all the rapidly dividing cells in the body, whether or not they were actually cancerous, in order to hopefully kill off all the cancer. It worked pretty well on many cancers but at a very high price in side effects such as hair loss, mouth sores, nausea, diarrhea, and fatigue.

    Radiation was also quite effective at killing cancer, but it also has numerous side effects such as burns, necrosis (tissue death), and fatigue. Some people receive Whole Brain Radiation (WBR) which treats large portions of the brain at once, while others get targeted SRS radiation (Stereotactic Radiation Surgery), targeted to very specific areas only.

    If I.V. chemotherapy is carpet bombing, then the oral medication of Targeted Therapy is precision bombing with Hunter/Seeker Missiles. It weaponizes various TKIs (Tyrosine Kinase Inhibitors) to strategically seek out and target only the mutated ALK cells. The results tend to be better and the side effects much less severe with Targeted Therapy.

    This is sometimes referred to as "oral chemotherapy" because you take pills instead of I.V. meds, but Targeted Therapy is not truly chemotherapy. The powerful TKIs of Targeted Therapies block the tyrosine kinase proteins and inhibit the growth of cancer, essentially switching the growth button from on to off.

    Which treatments are chosen depends on the staging of the cancer. Upon diagnosis, the oncologist assigns a "stage." Stages I-III are usually treated with surgery, chemotherapy, and/or radiation. Stage IV (where the cancer has already spread widely) is treated primarily with Targeted Therapy TKIs, with the addition of radiation and other therapies at times. 

    There has been an explosion in the development of TKIs in recent years. When summarizing treatment order, researchers use a common terminology. Drugs intended for first-time patients who have never had a treatment before ("treatment-naive") are called first-line treatments. People who have already had one TKI and have moved on to another because of disease progression are getting second-line treatments. People who have moved on after 2 TKIs are getting third-line treatments.

    Crizotinib (Xalkori) was the very first ALK TKI. It was approved by the FDA as first-line treatment for ALK+ in August 2011. Years later it has also been approved also for ROS1 mutations and may be soon for other mutations as well. Crizotinib is very effective against tumors in the body but does not cross the blood-brain barrier (BBB) well so it does not treat brain metastases very effectively.

    Ceritinib (Zykadia) was developed as a second-line treatment in order to cross the blood-brain barrier too. It was approved by the FDA in April 2014. It has now also been approved for first-line treatment as of May 2017. However, it has some heavy-duty side effects in some people.

    Alectinib (Alecsensa) was an even more effective TKI. It was approved as a second-line treatment by the FDA in December 2015. As of November 2017, it has also been approved as first-line treatment. It has been shown in several trials to effectively treat both body and brain metastases. 

    Brigatinib (Alunbrig) was also approved as second-line treatment by the FDA in April 2017. It is undergoing clinical testing as a first-line treatment as well and shows great promise in both body and brain. It is also sometimes used for EGFR patients, so it works well across a spectrum of patients.  

    Lorlatinib (Lobrena) is the latest TKI, and was approved in November 2018. Lorlatinib is a powerful drug that is effective against a number of different resistance submutations. It is approved for second- or third-line treatment and is especially helpful in brain metastases.

    Other TKIs are under development but still in clinical trials. The best sequence of TKIs is always evolving and many different versions have been tried. As of February 2019 in the U.S.A., the most common first-line treatment is Alectinib or Brigatinib. This treatment will hopefully last for some time, but how long varies from patient to patient. Then, when resistance develops, a second-line therapy is brought in, and when resistance develops again, a third-line therapy may be considered.

    The Next Step: Resistance


    After enough time on targeted therapy, resistance will develop. Cancer is sneaky that way. When this happens, doctors switch patients to a new TKI. The exact algorithm of which drugs and when they are prescribed will depend on your doctor's protocols and the approved drugs in that country, but some sequence of TKIs will usually work quite well for most patients before further resistance develops.

    Eventually, the original ALK mutation may develop a stubborn secondary mutation that does not respond to drugs that worked in the past. Some of the most common ALK submutations include:
    • L1196M
    • G1202R
    • I1175N
    • I1175S
    • C1156Y
    • L1198F
    This is why doctors should do additional molecular testing with Next Generation Sequencing (NGS) after resistance develops. Such testing will highlight which resistance mutations are occurring so the doctors know which medicine will best address the new submutation. For example, a common resistance mutation is G1202R, and Lorlatinib is the only TKI that addresses that mutation. Without NGS testing the doctor would not know about the G1202R and might try one of the other TKIs first.

    Another variation that sometimes occurs with progression is that the patient no longer tests positive for ALK because the TKIs are suppressing the ALK rearrangement. Or the cancer may have mutated to another form of cancer like squamous or even small-cell cancer. Or more than one type of cancer may be present at the same time. Cancer has many tricks up its sleeve.

    If all the TKIs including Lorlatinib cease to work, traditional doublet I.V. chemotherapy is often still effective. Doublet chemo uses two drugs, usually platinum-based carboplatin and pemetrexed (Alimta) chemotherapy, which seems particularly effective for gene fusion cancers like ALK and ROS1. Some oncologists may also add the PD-1 inhibitor pembrolizumab (Keytruda) or another drug but this is highly experimental right now.

    An exciting option in some areas is Local Consolidation Therapy (LCT). In LCT, targeted radiation or surgery is used proactively before progression occurs or gets very far. The idea is to "weed the garden," as Dr. Ross Camidge in Colorado puts it. In other words, don't wait for the weeds to run amok in the garden but jump on the weeds at the first sign and rip them out before they get a good foothold.

    A radical new treatment for lung cancer is immunotherapy, specifically checkpoint inhibitors. While these are a medical breakthrough for some types of lung cancer, sadly they have almost never worked for ALK patients. In fact, in some cases, checkpoint inhibitors have made cancer worse for ALK patients. So the picture is complex. The good news is that the ALK Positive patient group is funding research that will hopefully give us insight into how immunotherapy can become more effective for ALK patients.

    Clinical Trials


    Another option for treatment is Clinical Trials for new drugs or new treatment protocols. 

    As the graphic illustrates, the purpose and population studied in each Phase of a drug trial is different: 
    1. In Phase I of a drug trial, the population studied is very small and the purpose is to determine the best possible dosage of the drug
    2. In Phase II, the population studied is expanded and the purpose is to determine the safety and effectiveness of the drug
    3. In Phase III, the population studied is greatly expanded and the drug's effectiveness is compared against current standard of care treatment or against another therapy to see which is more effective
    4. In Phase IV, after FDA approval, data is collected on the drug in general use in large populations for information on long-term safety, effectiveness, and cost-effectiveness
    Clinical Trials are critical to the development of new treatment, but it can be difficult to recruit patients for it. Some people don't participate in Clinical Trials because they are afraid to try a new drug, but it's unusual for people to be in Phase I because it is so small. Most people join in later phases when there is more data on the drug and it looks promising. 

    Some people don't join Clinical Trials for practical reasons, like not having studies nearby, or because they don't have the budget to travel to another city for a Trial. However, requirements vary from study to study. Some involve a lot of travel, but some involve only minimal travel or being overseen by someone local. Keep your options open. Investigating the currently available Clinical Trials doesn't commit you to joining them. It just makes you aware of your options.

    One major advantage of Clinical Trials is that they are usually free to participants. Your drug, your monitoring scans, and many of your labs are usually free as part of the study funding. That can save patients many thousands of dollars, especially if they don't have great insurance. Other costs like travel are usually borne by patients, but there may be other resources out there that can help you cover or lessen these costs. Talk to the personnel in the trial and ask questions. 

    Patient participation in Clinical Trials is critical to keeping up the momentum of changes in the rapidly changing field of lung cancer treatment. Remember, it was through Clinical Trials that all the TKIs were developed that have so revolutionized ALK, EGFR, and ROS1 lung cancer treatment. Clinical Trials save lives, and let people who would not otherwise have lived survive and have more time with loved ones.

    Conclusion


    "Precision medicine" – individualizing patient treatments based on a genetic understanding of their cancer – is a quickly-evolving area of medicine. It will undoubtedly continue to change frequently as new drugs and treatments are developed. There are many new possibilities around the corner.

    When you are the person with Stage IV lung cancer, all the treatments can feel like too little, too late because we can't cure lung cancer yet. We can buy some time, though. It's important to remember that whatever "extra" length of life we are given, it is a blessing of the modern age. It is bonus time we wouldn't have gotten 20 years ago.

    Be realistic about your cancer prognosis, but don't give up hope. Take heart at the rate of change in the lung cancer field since 2007. Before that, there were very few effective treatments. Now we have an explosion of treatment possibilities with big things on the horizon. People are living longer. It's never enough until it's a cure, but at least the momentum is headed in the right direction.




    References

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