Targeted Therapy

TIP ... The Glossary has more information on the medical and scientific terms you'll see in this section.

Targeted cancer therapy is a type of treatment that uses drugs to attack cancer cells, including some kinds of lung cancers. As researchers have learned more about the changes in cells that cause cancer, they have been able to develop drugs that directly target some of these changes. These drugs target specific parts of cells and the signals that proteins send to cells that cause them to grow and divide uncontrollably.

Targeted therapy brochureTo help you understand and share this information, click here to download and print a booklet that summarizes the detailed information in the following sections.

Targeted cancer therapies are sometimes also called “precision medicines,” "molecularly targeted drugs," or "molecularly targeted therapies."

Find out more about the cell changes or mutations that they target, whether and how to get your tumor tested for mutations, whether targeted therapy might be a good treatment option for you, and what targeted therapy options are available now.

What is a mutation?

Illustration of cell mutation

All the organs and tissues in our bodies are made up of cells, and each of these cells contains thousands of genes. Genes are made up of DNA, which is a specific code that is used to ultimately make proteins that have specific functions for the cell. It is essential for each gene to have the correct DNA code, or instructions, for making its protein. When the DNA is correct, the protein is able to perform the correct function. When a gene has an error in its DNA, it is said to be changed or mutated. Mutations occur often, and normally the body can correct them. However, depending on where in a gene the change occurred, the small change may become part of the cell’s blueprint. Over time an accumulation of mutations can result in the formation of a tumor.1

The following video will help you understand mutations in lung cancer.

What Are the Different Types of Mutations Known to Cause Cancer?

One type of change seen in cancer is an activating mutation, in which the DNA sequence is changed. This can cause changes in the protein made by the gene so that it is always active. This may lead to uncontrolled cell growth.

Activating mutation

A fusion, or rearrangement, is another type of mutation. This occurs when a part of one gene fuses with or attaches to a part of another gene. The fused gene then produces a unique protein that promotes abnormal, uncontrolled cell growth.2

Gene protein fusion

Amplification means there are many more copies of a gene than normal. The overexpression then leads to increased protein activity and uncontrolled cell growth.2

Gene amplification

Different Mutations Seen in Lung Cancers

Lung cancer describes many different types of cancer that start in the lung or related structures. There are two different ways of describing what kind of lung cancer a person has:

  • Histology—what the cells look like under a microscope. Histological types include small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Subtypes of NSCLC include adenocarcinoma, squamous cell carcinoma (also known as squamous cell lung cancer), large cell carcinoma, and some rarer types
  • Biomarker profile (also called molecular profile, genetic profile, or signature profile)—the genetic characteristics, as well as any other unique biomarkers, found in a person’s cancer

Genetic biomarkers can be:

  • Acquired: present only in the tumor and not passed on to children
  • Inherited: present in all cells of the body and passed on to children

Most of the biomarkers that are helpful to making treatment decisions in lung cancer are acquired (sometimes called somatic). Inherited biomarkers are still being researched.

A person’s lung cancer may or may not have one of the many known mutations. For example, two patients may be treated with two different therapies because their own cancer does or doesn’t have a specific change or mutation. So far, researchers have identified over a dozen different mutations sometimes found in lung cancer, and they are continuing to look for more. The specific changes are also known as biomarkers.

Right now scientists have the most information about mutations in the histologic subtype of lung cancer called adenocarcinoma.3

Biomarker profile of adenocarcinoma

Researchers are also making progress in understanding mutations in squamous cell lung cancer.4,5

Biomarker profile of squamous cell lung cancer

Mutations in small cell lung cancer are also being studied, but at this time there is the least knowledge about mutations in this type of lung cancer, in part because it is less common than the other two. Mutations are being studied for all lung cancer types, and more information is being presented at every medical conference, so expect more updates.

In this video, Dr. Joel Neal of Stanford University Medical Center explains what “wild type” mutations mean and where the name comes from.

How is biomarker testing performed?

To find out if targeted cancer therapy makes sense for an individual with lung cancer, that person’s tumor tissue will be tested. The goal is to determine whether or not an appropriate target is present. The following video describes diagnostic testing for mutations in lung cancer.

A sample is taken from either an entire tumor that has been removed by a surgeon, or part of a tumor is collected by biopsy. Which approach is used depends on the stage of lung cancer and the person’s overall health. A tumor sample is sent to a laboratory that can test it for mutations. Test results are generally available within 10 to 14 days. Biomarker testing can be done on both primary tumors and metastatic tumors.6

When there is not enough of a tumor sample to test for multiple mutations, testing should be prioritized based on the most likely mutations and whether there is an available Food and Drug Administration (FDA)-approved drug treatment. Most insurance plans will only pay for testing related to an FDA-approved treatment. Therefore, at this time, when there is only a limited amount of tumor sample, tumors should be tested for the EGFR mutation, the ALK mutation, and the ROS1 mutation.6

Multiplex testing has the ability to identify multiple mutations at the same time. This may allow more tests to be done on a smaller tumor sample than if individual tests are done. For example, one study is looking at a particular laboratory test that has the ability to identify 10 known mutations in NSCLC.7

Currently, the following drugs are FDA-approved in the US for patients with known mutations. They are also available in many other countries:

  • EGFR:  afatinib (Gilotrif®), erlotinib (Tarceva®), gefitinib (Iressa®), and osimertinib (TagrissoTM)
  • ALK:  crizotinib (Xalkori®), alectinib (Alecensa®), and ceritinib (ZykadiaTM)
  • ROS1:  crizotinib (Xalkori®)

For patients with these and other mutations, a clinical trial for a new drug targeting that mutation may also be an option. More information about these drugs can be found below.

Who should have their tumor tested and when?

The decision to have your tumor tested and when depends on a number of factors, including your type and stage of lung cancer.

There are guidelines for deciding which patients should have EGFR and ALK biomarker testing.* The goal is to match patients with approved drugs that target those mutations. Updated guidelines for these mutations and others, including ROS1, are currently in development.

Type of Lung Cancer Guidelines for Biomarker Testing
Stage I, II, or III adenocarcinoma Testing for the EGFR and ALK mutations at the time of diagnosis is encouraged, but the decision should be made on an individual basis with your physicians
Stage IV adenocarcinoma, or adenocarcinoma that has recurred or progressed after an initial diagnosis of stage I, II, or III lung cancer in patients who were not previously tested Tumors should be tested for EGFR and ALK mutations
Any stage squamous cell lung cancer or small cell lung cancer
  • If a tumor is completely removed and there is no adenocarcinoma component, testing for EGFR and ALK mutations is not recommended
  • If the specimen is from a more limited sampling technique, such as a biopsy, testing may be performed in cases showing only squamous or small cell lung cancer cells. This is because it is possible that a tumor may have adenocarcinoma cells mixed in that were missed by the biopsy6,7

*Jointly developed by the International Association for the Study of Lung Cancer (IASLC), the College of American Pathologists (CAP), and the Association for Molecular Pathology (AMP).

When deciding whether to have your tumor tested, you may also want to consider that mutations in genes other than ALK, EGFR, and ROS1 have been found in both adenocarcinoma and squamous cell carcinoma.

Testing to identify other possible mutations in the tumor may help you find clinical research studies. These studies are testing new treatments for mutations in other types of lung cancer. Therefore, you may consider biomarker testing for other mutations even if you don’t fit into the ALK, EGFR, or ROS1 testing categories.

Ultimately, any decision to test for biomarkers should be made together by you and your physician(s). This should be a part of the discussion with both your oncologist and surgeon. Your oncologist may recommend additional testing at different points of your treatment process.

As noted earlier, mutations other than ALK, EGFR, and ROS1 have been identified in types of lung cancer other than adenocarcinoma, particularly in squamous cell carcinoma. Drugs that target many of those mutations are being tested through clinical trials, so discussion of biomarker testing makes sense for people with pure squamous cell carcinoma as well.

In addition, multiplex testing to identify other possible mutations in the tumor may help a patient find clinical research studies.

Questions to ask your health care team if you are considering biomarker testing:

  • How long will it take to get the biomarker test results, and is waiting for the results to begin treatment an option based on the extent of my disease?
  • Will insurance pay for the test?
  • What are the side effects of other treatment options that are available?8

In this video, Dr. Joel Neal of Stanford University Medical Center talks about whether patients with early-stage lung cancer should get their tumor tested for mutations and how to find a clinical trial that makes sense for them.

What are targeted cancer therapies?

Targeted cancer therapies are sometimes also called:

  • Precision medicines
  • Molecularly targeted drugs
  • Molecularly targeted therapies

As researchers have learned more about the mutations that cause cancer in cells, they have been able to develop drugs that target some of these mutations. Targeted cancer therapies are a type of biological therapy that aims to target cancer cells directly. They target certain parts of cells and the signals that cause cancer cells to grow uncontrollably and thrive. These drugs are often grouped by how they work or what part of the cell they target.

Targeted therapies are aimed at specific pathways that tumor cells use to thrive, blocking them in the same way that blocking a car’s fuel line would keep it from running properly. The advantage of such precise treatments is that they can target the root cause of why a tumor is growing, which may make them more effective.9

Available targeted therapies

Targeted therapies are currently approved by the US Food and Drug Administration (FDA) for people who have either anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), or ROS1 mutations. Clinical research studies are currently studying promising drugs to target many other mutations.

All of the drugs that have already been studied and FDA-approved belong to a class of drug called tyrosine kinase inhibitors (TKIs).

Tyrosine kinases are specific enzymes that may signal cancer cells to grow. Tyrosine kinase inhibitors (TKIs) are targeted therapies that block these cell signals. By blocking these signals, they keep the cancer from getting bigger and spreading. TKIs are named for the enzyme they block. The first TKIs for which there has been FDA approval are:

  • EGFR inhibitors
  • ALK inhibitors
  • ROS1 inhibitor9

EGFR (epidermal growth factor receptor) inhibitors

EGFR is a protein found in abnormally high levels on the surface of some cancer cells. Mutations involving EGFR can lead to uncontrolled cancer cell growth and survival.9

Approximately 10% of patients with lung adenocarcinoma in the US and 35% in East Asia have tumors with an EGFR mutation. Regardless of ethnicity, EGFR mutations are more often found in tumors of female non-smokers.3

This video provides an introduction to EGFR inhibitors. Please note that since it was published in March 2015, gefitinib (Iressa®) and osimertinib (TagrissoTM) have been approved for use in the United States as well. Information on these two drugs appears on the website below.

Marketed EGFR inhibitors,3 also known as EGFR tyrosine kinase inhibitors (TKIs)

There are currently three marketed EGFR inhibitors that are approved as first-line treatment for patients with metastatic EGFR-positive non-small cell lung cancer:

  • Afatinib (GilotrifTM)10
  • Erlotinib (Tarceva®)11
  • Gefitinib (Iressa®)12

Afatanib is also approved for the treatment of patients with metastatic squamous cell NSCLC who have progressed after treatment with platinum-based chemotherapy.10

Erlotinib is also approved as maintenance or second-line or greater therapy for EGFR-positive patients with metastatic NSCLC whose cancer has progressed after at least one prior chemotherapy regimen.11

Another treatment for EGFR-positive patients is:

  • Osimertinib (TagrissoTM)
    • For metastatic EGFR-positive NSCLC that also has the T790M mutation, and that
    • Has grown or spread on or after another EGFR TKI therapy.13

Read more about this in “Resistance to tyrosine kinase inhibitors (TKIs).”

In addition, many other EGFR inhibitors are currently being studied in clinical trials.

How do EGFR inhibitors work?

These drugs work by blocking the signals that activate EGFR. This results in decreased tumor growth and survival.9

How are they administered?

Most EGFR inhibitors are pills taken by mouth once a day.10,11,12,13

What are the side effects of EGFR inhibitors?

The most common side effect seen with EGFR inhibitors is an acne-like rash on the scalp, face, neck, chest, and upper back. This occurs because normal skin cells have a lot of EGFR, and they must grow quickly to maintain the skin’s surface layer. Drugs that target EGFR also turn off the signal for skin cells to grow normally and make it harder for them to retain moisture.

Other common side effects include:

  • Pruritus
  • Diarrhea
  • Stomatitis
  • Loss of appetite
  • Weakness
  • Cough10

More serious side effects that have been seen rarely with one or more of the EGFR inhibitors are:

  • Interstitial lung disease
  • Liver and kidney damage
  • Eye inflammation
  • Severe skin lesions
  • Bleeding problems10,11,12

When you start a new EGFR inhibitor, you should discuss with your doctor:

  • Which potential side effects to expect
  • What can be done to manage them
  • Which side effects are serious and need to be reported immediately

Get tips on managing treatment-related side effects.

Where do EGFR inhibitors fit in the lung cancer treatment plan?

Sometimes treatment with an EGFR inhibitor will be the only treatment a patient receives. However, in most cases, an EGFR inhibitor is used before or after chemotherapy, surgery, and/or radiation therapy.

ALK (anaplastic lymphoma kinase) inhibitors

An ALK rearrangement is a fusion between two genes: ALK and another gene, with the most common being echinoderm microtubule-associated protein-like 4 (EML4). The fusion of these two genes produces an abnormal ALK protein that causes cancer cells to grow and spread.

The fusion between ALK and EML4 is more common in younger patients (median age at diagnosis is 52 years), in people who never smoked or light smokers, and in those with adenocarcinomas. It has rarely been found in patients with squamous cell carcinoma. Similar frequencies of the ALK fusion gene (3%-7%) have been reported in Asian and Western populations among patients with lung adenocarcinoma, unlike what we see with EGFR mutations.3,14

This video provides an introduction to ALK inhibitors.

Marketed ALK inhibitors, also known as ALK Tyrosine Kinase Inhibitors (TKIs)

There are currently three marketed ALK inhibitors:

  • Crizotinib (Xalkori®):  Approved for patients with metastatic NSCLC who are ALK positive15
  • Alectinib (Alecensa®): Approved for patients with metastatic NSCLC who have progressed on or are intolerant to crizotinib16
  • Ceritinib (Zykadia™):  Approved for patients with metastatic NSCLC who have progressed on or who are intolerant to crizotinib17

In addition, many other ALK inhibitors are currently being studied in clinical trials.

How does an ALK inhibitor work?

It works by blocking the signals that the abnormal ALK proteins send to cells to grow and divide uncontrollably. This stops the growth and spread of the cancer cells.9

How is it administered?

  • Crizotinib (Xalkori®) is given as a pill 2 times a day, with or without food.15
  • Alectinib (Alecensa®) is given as a pill 2 times a day, with food.16
  • Ceritinib (ZykadiaTM) is given as a pill once a day and cannot be taken within 2 hours of a meal.17

What are the side effects of the ALK inhibitors?

The side effects of the ALK inhibitors can be very different for the different drugs and in different patients.  The common side effects of ALK inhibitors as a group include nausea, diarrhea, vomiting, constipation, swelling of the hands and feet, feeling tired, decreased appetite, muscle pain, abdominal pain, and liver damage (as shown by abnormal blood tests related to liver function).15,16,17 Some of these side effects can be improved by reducing the dose of ALK inhibitors.

The most common side effect caused by crizotinib is difficulty with vision. This includes trouble looking at light, blurred vision, double vision, seeing flashes of light, or new and increased floaters.15 These visual side effects usually come and go very quickly and will go away if crizotinib is stopped. People almost never stop treatment with crizotinib because of vision problems.

Alectinib and ceritinib do not have as frequent visual side effects, but they have higher rates of some other common side effects.16,17

Low testosterone is one source of fatigue in patients being treated with crizotinib. This can also lead to sexual dysfunction and depression. Researchers have found that hormone replacement therapy is an effective method of managing these side effects.18

When you start a new ALK inhibitor, you should discuss with your doctor:

  • Which potential side effects to expect
  • What can be done to manage them
  • Which side effects are serious and need to be reported immediately

Get tips on managing treatment-related side effects.

Where does an ALK inhibitor fit in the lung cancer treatment plan?

Sometimes treatment with an ALK inhibitor will be the only treatment a patient receives. However, in most cases, ALK inhibitors are used before or after chemotherapy, surgery, and/or radiation therapy.

ROS1 inhibitor

A ROS1 rearrangement is a fusion between two genes, ROS1 and another gene. As with ALK, the fusion of the two genes produces an abnormal protein that causes cancer cells to grow and spread.1

About 1%-2% of patients with lung adenocarcinoma in the US and 2%-3% in East Asia have tumors with a ROS1 mutation. ROS1 fusions are more commonly found among younger patients (median age at diagnosis is 50 years), females, never-smokers, and patients with adenocarcinoma.19,20,21,22,23

Marketed ROS1 inhibitor, also known as ROS1 tyrosine kinase inhibitor (TKI)

There is one tyrosine kinase inhibitor that has been approved for patients with metastatic NSCLC whose tumors are ROS1-positive. This is crizotinib (Xalkori®), a TKI that is also used for patients with ALK-positive tumors.15

Other ROS1 inhibitors are currently being studied in clinical trials.

How does a ROS1 inhibitor work?

It works by blocking the signals that the abnormal ROS1 proteins send to cells to grow and divide uncontrollably. This stops the growth and spread of the cancer cells.9

How is it administered?

Crizotinib (Xalkori®) is given as a pill 2 times a day, with or without food.15

What are the side effects of the ROS1 inhibitor?

The side effects of crizotinib on patients who are ROS1-positive are in general consistent with those of patients who are ALK-positive. The most common side effects are visual problems, diarrhea, nausea, swelling of the hands and feet, constipation, vomiting, and liver damage (as shown by abnormal blood tests related to liver function), feeling tired, changes in taste, and dizziness. Most of these side effects are mild and not permanent.23

When you start on crizotinib, you should discuss with your doctor:

  • Which potential side effects to expect
  • What can be done to manage them
  • Which side effects are serious and need to be reported immediately

Get tips on managing treatment-related side effects.

Where does the ROS1 inhibitor fit in the lung cancer treatment plan?

Sometimes treatment with crizotinib will be the only treatment a ROS1-positive patient receives. However, in most cases, crizotinib is used before or after chemotherapy, surgery, and/or radiation therapy.

Resistance to tyrosine kinase inhibitors (TKIs)

The biggest challenge of TKIs is that patients with lung cancer who initially benefit from them eventually develop resistance. Acquired resistance is defined* as disease progression after initial benefit with a targeted cancer therapy.24

Cancer cells are clever enough to bypass roadblocks to their survival and often mutate to overcome the effects of targeted drugs. The most common way adenocarcinomas become resistant to EGFR inhibitors is by mutating to a drug-resistant state that stops the drugs from working. Lung cancers with an ALK or ROS1 rearrangement normally have good responses to inhibitors. However, they also eventually become resistant to the effects of the drugs.

Another way a tumor can become resistant to EGFR inhibitors is by activating a different pathway. In a small number of cases, the adenocarcinoma may transform into small cell lung cancer.25

Doctors and researchers are working to overcome resistance in tumors and to keep the TKIs effective against cancer for longer periods of time. Their approaches include:

  • Prescribing multiple enzyme inhibitors at the same time in case a different mutation in the cell has been activated
  • Developing the next generation of enzyme inhibitors that will inhibit not only the activity of the mutated gene but also the mutant form it could change into.26

If a patient’s cancer has grown after treatment with an EGFR TKI, a decision needs to be made about the next treatment option. The doctor will usually recommend that a biopsy be done of one of the tumors that is growing. The tumor will need to be tested to see if there is a new mutation in EGFR. If the EGFR T790M mutation is present (it is found in about two-thirds of patients who have this biopsy), the doctor may recommend the next-generation EGFR inhibitor, osimertinib (TagrissoTM), or a clinical trial.13

Several next-generation inhibitors have already been approved, including ceritinib (ZykadiaTM) and alectinib (Alecensa®), for ALK-positive NSCLC.16,17

*According to Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria.


Hear more about managing resistance to TKIs from experts on the topic: Dr. Greg Riely of Memorial Sloan Kettering Cancer Center and Dr. Lecia Sequist of Massachusetts General Hospital, with moderator Dr. Jared Weiss of University of North Carolina School of Medicine in Chapel Hill.

This was recorded on February 21, 2014, at the 14th Annual Targeted Therapies of the Treatment of Lung Cancer meeting, sponsored by the International Association for the Study of Lung Cancer (IASLC). It was recorded in partnership with Global Resource for Advancing Cancer Education (GRACE). Please note that since it was recorded, osimertinib (TagrissoTM), alectinib (Alecensa®), and ceritinib (ZykadiaTM) have been approved for use in the US. These are drugs that are used when there is progression with the first-line treatment.

Which mutations identified in lung cancer are currently being studied in clinical trials?

Currently clinical trials are open for many drugs that inhibit the effect of mutations seen in NSCLC. The targeted treatments are being studied alone and in combination with other targeted agents, chemotherapy, and radiation therapy.

As the number of known mutations in lung cancer tumors increases, so does the number of drugs being developed to target them. Drugs that are currently being studied act against the following mutations:

  • AKT1
  • ALK
  • BRAF V600E
  • BRAF (non-V600E), KRAS, NRAS, or MEK
  • DDR2
  • EGFR
  • FGFR1
  • HER2
  • KRAS
  • MEK1
  • MET
  • NTRK1
  • PDGFR
  • PIK3CA
  • PTEN
  • RET
  • ROS1

Dr. Charles Rudin of Memorial Sloan Kettering Cancer Center explains BRAF and other RAF mutations, their role with KRAS, and how they are being studied in clinical trials.

Dr. Joel Neal of Stanford University Medical Center explains FGFR, a mutation being studied in clinical trials for people with squamous cell lung cancer.

If you are considering participating in a clinical trial, start by asking your health care team whether there is one that might be a good match for you in your geographic area. In addition, there are several resources to help you find one that may be a good match.

Information about available clinical trials may be found through the resources detailed below. The first is a comprehensive resource with trained experts who help you navigate clinical trials. The next three include trials for all cancers, not just lung cancer. The last three focus on people with mutations.

In addition, if you are interested in a specific drug or other treatment that is being developed, you can often find information about studies for that drug on the website of the company developing it.

  • EmergingMed: www.emergingmed.com/networks/LUNGevity
    • LUNGevity partners with this free clinical trials matching service to help you with the decision of whether to participate in a clinical trial.
    • EmergingMed helps you identify lung cancer clinical trials for which you may be eligible
    • Clinical trial navigators are available Monday through Friday from 8:30am to 6:30pm ET at 800-698-0931
  • US National Institutes of Health:  www.clinicaltrials.gov
  • National Cancer Institute (NCI):  www.cancer.gov/clinicaltrials/search
  • Coalition of Cancer Cooperative Groups: www.cancertrialshelp.org/cancer-trial-search
  • My Cancer Genome:  www.mycancergenome.org
    • My Cancer Genome gives up-to-date information on what mutations make cancers grow and related treatment options, including available clinical trials
  • Lung Cancer Mutation Consortium (LCMC):   www.golcmc.com
    • Composed of 16 leading cancer centers across the country
    • LCMC’s goal is to examine the tumors of patients who have a type of advanced (stage IIIB or IV) non-small cell lung cancer called adenocarcinoma, and match those patients to the best possible therapies, including clinical trials
  • Lung Cancer Master Protocol (Lung -MAP):  www.lung-map.org
    • For patients with squamous cell carcinoma
    • LUNG-MAP is a collaboration of many research sites across the country. They use a unique approach to match patients to one of several drugs being developed

Learn more about clinical trials here.

Questions to ask your health care team about targeted therapy

Print this list

  1. Why do you recommend a targeted cancer therapy for me?
  2. What mutation do I have?
  3. What kind of targeted cancer therapy will I get?
  4. Will targeted cancer therapy be my only treatment or will it be combined with another treatment?
  5. How often will I take this therapy and for how long?
  6. How and when will I know if the treatment is working?
  7. How often do I need to be seen between treatments for a physical exam and/or lab work?
  8. Can I expect to see changes in my lab results while on this treatment?
  9. Are there any tests or procedures I will need during the treatment?
  10. What side effects can I expect?
  11. What can I do to manage these side effects?
  12. How will this treatment affect my daily life? Will I be able to work, exercise, and perform my usual activities?
  13. What tests will I need after treatment is completed?
  14. Are there any long-term health issues I should expect from treatment with targeted therapy?
  15. How much will my treatment cost?

Updated November 2, 2016


References

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  6. Bankhead C. Guide for Lung Cancer Gene Tests Published. Medpage Today website. http://www.medpagetoday.com/HematologyOncology/LjngCancer/38263. Published April 5, 2013. Accessed March 2, 2016.
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  8. Lindeman NI, et al. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors. The Journal of Molecular Diagnostics, 2013; 15(4); pp 415-453. http://www.jto.org/article/S1556-0864%2815%2932867-7/fulltext. Accessed March 2, 2016.
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  10. Gilotrif® (afatinib) tablets [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT. http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Gilot.... Revised April 2016. Accessed October 26, 2016.
  11. Tarceva® (erlotinib) tablets [package insert]. OSI Pharmaceuticals, LLC. Northbrook, IL. http://www.gene.com/download/pdf/tarceva_prescribing.pdf. Revised October 2016. Accessed October 26, 2016.
  12. Iressa® (gefitinib) tables [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206995s000lbl.pdf. Revised July 2015. Accessed March 2, 2016.
  13. TagrissoTM (osimertinib) tablets [package insert]. AstraZeneca Pharmaceuticals LP. Wilmington, DE. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf. Revised November 2015. Accessed March 2, 2016.
  14. Shaw A, Solomon B. Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer. UptoDate website. http://www.uptodate.com/contents/anaplastic-lymphoma-kinase-alk-fusion-o.... Updated January 12, 2016. Accessed March 2, 2016.
  15. Xalkori® (crizotinib) capsules [package insert]. Pfizer, Inc. New York, NY. http://labeling.pfizer.com/showlabeling.aspx?id=676. Revised March 16, 2016. Accessed March 23, 2016.
  16. Alecensa® (alectinib) capsules [package insert]. Genentech, Inc. South San Francisco, CA. http://www.gene.com/download/pdf/alecensa_prescribing.pdf. Revised December 2015. Accessed March 2, 2016.
  17. ZykadiaTM (ceritinib) capsules [package insert]. Novartis. Basel, Switzerland. http://www.pharma.us.novartis.com/product/pi/pdf/zykadia.pdf. Revised July 2015. Accessed March 2, 2016.
  18. Weickhardt AJ, Doebele RC, et al. Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. Cancer, 2013; 119(13):2383-2390. doi:10.1002/cncr.28089. http://onlinelibrary.wiley.com/doi/10.1002/cncr.28089/full. Accessed March 2, 2016.
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