Targeted Therapy

Targeted therapy is a type of treatment that uses drugs or other substances to attack cancer cells, including some kinds of lung cancers. As scientists have learned more about the gene changes, or mutations, in cells that cause cancer, they have been able to develop drugs that directly target some of these mutations. 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, you can request our free booklet that summarizes the detailed information in the following sections.

Targeted therapies are sometimes also called "biomarker-driven therapies" "precision medicines,” "molecularly targeted drugs," or "molecularly targeted therapies."

Find out below about the mutations that can cause lung cancer, how to get your tumor tested for mutations, what targeted therapy options are available now, and whether targeted therapy might be a good treatment option for you.

What is a driver 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 genesCoded instructions within a cell that control how the cell grows in a systematic and precise way. Genes are made up of DNAThe molecules inside cells that carry genetic information and pass it from one generation to the next; also called "deoxyribonucleic acid", which is a specific code that is used to ultimately make proteins that have specific functions in cells. 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 mutated. Mutations occur often, and normally the body can correct them. However, depending on where in a gene the mutation occurred, the mutation may become part of the cell’s blueprint. Over time an accumulation of mutations can result in the formation of a tumorAn abnormal mass of tissue that results when cells divide more than they should or do not die when they should.1 Mutations that can cause cancer are called driver mutations.

Mutations can be:
• Acqured (also called somatic): Present only in the tumor and not passed on to childrren
• Inherited (also called germline): Present in all cells of the body and passed on to children

Virtually all of the mutations that occur and inform treatment decisions in lung cancer are acquired. Inherited mutations are still being researched in lung cancer.1

All of the targeted therapies discussed here are for acquired mutations.

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

Several types of driver mutations cause cancer. Some of these include:

• Activating mutation: An activating mutation is a change in the DNA sequence that 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

Examples of activating mutations in lung adenocarcinomaOne type of non-small cell lung cancer that usully develops in the cells lining the lungs. It has an increased incidence in smokers and is the most common type of lung cancer seen in nonsmokers are an L858R substitution mutation or exon 19 deletion in the epidermal growth factor receptor (EGFR) gene and the V600E mutation in the BRAF gene.3

• Fusion:  Fusion, or rearrangment, 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

Examples of fusion genes in lung adenocarcinoma include the ALK-EML4 and the CD74-ROS1 fusion genes.4,5

Amplification: Amplification means that there are many more copies of a gene than normal. The overexpressionThe expression of too many copies of a protein or other substance then leads to increased protein activity and uncontrolled cell growth.2

Gene amplification

Examples of genes that can be amplified in lung adenocarcinoma include the HER2 and the MET genes.3

• Deletion: Deletion means part of or the entire gene is missing in the cancer cells. The deletion then leads to reduced levels of protein being produced by the cancer cell.2

Deletion

Examples of deleted genes in small cell lung cancer (SCLC) include the TP53 and the RB genes.6

Driver Mutations Seen in Lung Cancers

Lung cancerCancer that begins in tissues of the lung, usually in the cells lining air pasages 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:

  • Biomarker profileThe genomic characteristics, as well as any other unique biomarkers, found in a person's cancer. The information is used to identify and create targeted therapies that are designed to work for a specific cancer tumor profile (also called molecular profile, genomic profile, or signature profile)—the genomic characteristics, as well as any other unique biomarkers, found in a person’s cancer
  • Histology—what the cells look like under a microscope. Histological types include small cell lung cancer (SCLC)A fast-growing cancer that forms in tissues of the lung and can spread to other parts of the body. Named small for how the cancer cells look under a microscope and non-small cell lung cancer (NSCLC)A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell lung cancer, large cell lung cancer, and adenocarcinoma. Non-small cell lung cancer is the most common kind of lung cancer. Subtypes of NSCLC include adenocarcinoma, squamous cell carcinomaA type of non-small cell lung cancer that usually starts near a central bronchus. It begins in squamous cells, which are thin, flat cells that look like fish scales. Also called squamous cell carcinoma (also known as squamous cell lung cancer), large cell carcinomaLung cancer in which the cells are large and look abnormal when viewed under a microscope, and some rarer types

A person’s lung cancer may or may not have one of the many known driver mutations.  So far, scientists have identified more than 20 different driver mutations that can be found in non-small cell lung cancer (NSCLC) and small cell lung cancer, and they are continuing to look for more.

These driver mutations are biomarkers that can be identified through molecular (or genomic) testing of a lung cancer. This testing is typically performed on a piece of tumor taken from a biopsy or, in some cases, through a blood test or liquid biopsy. (Read below for more information about liquid biopsies.) Their presence may determine whether a patient will be prescribed one of the targeted therapies approved by the US Food and Drug Administration (FDA) or be potentially eligible for a clinical trialA type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical research trial or study.

Right now scientists have the most information about driver mutations in the histologic subtype of lung cancer called adenocarcinoma.3,7

The driver mutations that currently have targeted therapies approved by the FDA include ALK, EGFR, ROS1, and BRAF V600E.

 Driver mutations in adenocarcinoma

Researchers are also making progress in understanding mutations in squamous cell lung cancer, although there are no FDA-approved drugs yet for these.3,8,9,10

Driver mutations in squamous cell lung cancer

Driver mutations in small cell lung cancer and other types of lung cancer are also being studied. However, there are as yet no targeted therapy drugs that are FDA-approved for them. This may change, so check with your doctors.11

What are targeted  therapies?

Targeted therapies are sometimes also called:

  • Biomarker-driven therapies
  • Precision medicines
  • Molecularly targeted drugs
  • Molecularly targeted therapies

Targeted therapies are a type of treatment that targets specific parts of cancer cells and the signals that proteins send to cancer cells that cause them to grow and divide uncontrollably.12 These drugs are often grouped by how they work or what part of the cell they target.

Tyrosine kinase inhibitors (TKIs)

All of the targeted therapy drugs that have aleady been FDA-approved for lung cancer belong to a class of drugs called tyrosine kinase inhibitors (TKIs)A type of targeted therapy that blocks the action of enzymes called tyrosine kinases in order to keep cancer cells from growing.

Tyrosine kinasesA specific enzyme produced by the body to control cell functions, including cell signaling, growth, and division. These enzymes may be too active or found at high levels in some types of cancer cells are specific proteins that act as enzymesA special protein that the body produces to control its cells and carry out chemical reactions quickly. Sometimes enzymes signal cancer cells to grow that may signal cancer cells to grow. The proteins encoded by the ALK, EGFR, ROS1, and BRAF genes are all examples of tyosine kinases. Tyrosine kinase inhibitors are targeted therapies that block these cell signals.13 By blocking the signals, they keep the cancer from growing and spreading. TKIs are named based on the enzyme, or protein, that they block. The driver mutations for which there are FDA-approved drugs on the market are:5

  • ALK
  • EGFR sensitizing mutationsMutation in a gene that responds to tyrosine kinase inhibitors; also called non-resistant mutation
  • ROS1
  • BRAF V600E

In addition, clinical trials are currently studying promising drugs to target other driver mutations.

ALK (anaplastic lymphoma kinase) inhibitors

An anaplastic lymphoma kinase (ALK) rearrangement is a fusionA gene made by joining parts of two different genes between two genes: ALK and, most commonly, echinoderm microtubule-associated protein-like 4 (EML4)A gene that when combined with the anaplastic lymphoma kinase (ALK) gene produces an abnormal protein that leads to cancer cell growth. (Note that the ALK gene can rarely be fused to other genes.) The fusion of these two genes produces an abnormal ALK protein that causes cancer cells to grow and spread.

About 7% of patients with lung adenocarcinoma in the US have tumors with an ALK mutation. A similar frequency has been reported in Asian populations. 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 adenocarcinomas. It has rarely been found in patients with squamous cell carcinoma.3, 7,14

Approved ALK INHIBITORS, ALSO KNOWN AS ALK TYROSINE KINASE INHIBITORS (TKIS)

There are currently five FDA-approved ALK inhibitors:

  • Crizotinib (Xalkori®): Approved for patients with metastaticHaving to do with metastasis, which is the spread of cancer from the primary site, or place where it started, to other places in the body NSCLC who are ALK-positive as detected by an FDA-approved test15
  • Ceritinib (Zykadia®)Approved for patients with metastatic NSCLC who are ALK-positive as detected by an FDA-approved test16
  • Alectinib (Alecensa®): Approved for patients with metastatic NSCLC who are ALK-positive as detected by an FDA-approved test17
  • Brigatinib (Alunbrig®): Approved for patients with metastatic ALK-positive NSCLC who have progressed on or who are intolerant to crizotinib18
  • Lorlatinib (Lorbrena®): Approved for patients with metastatic ALK-positive NSCLC whose disease has progressed on crizotinib and least one other ALK inhibitor for metastatic disease or whose disease has progressed on alectinib or ceritinb as first-line therapy19

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

HOW DO ALK INHIBITORs WORK?

ALK inhibitors work 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.20

HOW are aLK inhibitors ADMINISTERED?

  • Crizotinib (Xalkori®) is given as a pill 2 times a day, with or without food.15
  • Ceritinib (Zykadia®) is given as a pill once a day and must be taken at least 1 hour before a meal or at least 2 hours after a meal.16
  • Alectinib (Alecensa®) is given as a pill 2 times a day, with food.17
  • Brigatinib (Alunbrig®) is given as a pill once a day, with or without food.18
  • Lorlatinib (Lorbrena®) is given as a pill once a day.19

WHAT ARE THE SIDE EFFECTS OF THE ALK INHIBITORS?

The side effects of the ALK inhibitors differ by drug and by patient.15,16,17,18,19

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

  • Nausea
  • Diarrhea
  • Vomiting
  • Constipation
  • Fatigue

Some of these side effects can be improved by reducing the dose of ALK inhibitors.15,16,17,18,19,21 

Some serious but rare side effects of ALK inhibitors as a group include:

  • Liver problems
  • Breathing problems (pneumonitisInflammation of the lungs that may be caused by disease, infection, radiation therapy, allergy, or irritation of lung tissue by inhaled substance)
  • Abnormal heartbeats

Overall, these drugs are well tolerated.

In addition, crizotinib (Xalkori®) has unique vision-specific side effects. These include:15

  • Trouble looking at light
  • Blurred vision
  • Double vision
  • Seeing flashes of light
  • New and increased floatersA bit of optical debris (as a dead cell or cell fragment) in the vitreous body or lens that may be perceived as a spot before the eye 

Low testosterone is one source of fatigue in patients being treated with crizotinib (Xalkori®). 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.22

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 DO ALK INHIBITORs 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, together with, or after other treatments, which can include chemotherapy, surgery, and/or radiation therapyThe use of high-energy radiation from X-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Also called irradiation and radiotherapy.

EGFR (epidermal growth factor receptor) inhibitors

Epidermal growth factor receptor (EGFR) is a protein found in abnormally high levels on the surface of some cancer cells. Driver mutations involving EGFR can lead to uncontrolled cancer cell growth and survival.20

Approximately 10% of patients with NSCLC in the US and 35% in East Asia have tumors with an EGFR driver mutation. Regardless of ethnicity, EGFR mutations are more often found in tumors of female nonsmokers. Most commonly, these patients have adenocarcinoma.7

► Approved EGFR inhibitors, also known as EGFR tyrosine kinase inhibitors (TKIs)

There are currently five FDA-approved EGFR inhibitors, which are also known as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs).

All of these are approved for first-line treatmentThe first treatment given for a disease. It is often part of a standard set of treatments, such as surgery followed by chemotherapy and radiation. When used by itself, first-line treatment is the one accepted as the best treatment. If it doesn't cure the disease or it causes severe side effects, other treatment may be added or used instead; erlotinib (Tarceva®) and osimertinib (Tagrisso®) are also approved for additional treatments:

  • Afatinib (Gilotrif®):23 Approved for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR non-resistant (sensitizing) mutations as detected by an FDA-approved test. The most common of these are the exon 19 deletions and the exon 21 (L858R) substitution mutations. The more rare mutations are S768L, L861Q, and G719X.
  • Dacomitinib (Vizimpro®):24 Approved for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
  • Erlotinib (Tarceva®):25Approved for the treatment of patients with EGFR-positive metastatic NSCLC. This includes patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test who are receiving first-line or maintenance treatmentTreatment that is given to help keep cancer from coming back after it has disappeared following the initial therapy. It may include treatment with drugs, vaccines, or antibodies that kill cancer cells, and it may be given for a long time, or second- or greater-line treatment after progression following at least one prior chemotherapy regimen.
  • Gefitinib (Iressa®):26 Approved for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.
  • Osimertinib (Tagrisso®):27 Approved for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. It is also approved for second-line treatment of patients with metastatic NSCLC whose tumors are (EGFR) T790M-positive, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy. 

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

How do EGFR inhibitors work?

These drugs work by blocking the signals that activate the EGFR protein, resulting in decreased tumor growth and survival.20

How are EGFR inhibitors administered?

Afatanib (Gilotrif®) is given as a pill once a day, 1 hour before or 2 hours after a meal.23
Dacomitinib (Vizimpro®) is given as a pill once a day, with or witout food.24
Erlotinib (Tarceva®) is given as a pill once a day on an empty stomach.25
Gefinitb (Iressa®) is gien as a pill once day, with or without food.26
Osimertinib (Tagrisso®) is given as a pill once a day, with or without food.27

What are the side effects of EGFR inhibitors?

A very common side effect of 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.23,24,25,26,27

Other common side effects of EGFR inhibitors as a group include:23,24,25,26,27

  • Itching (PruritusItching of the skin)
  • Diarrhea
  • Mouth sores (StomatitisInflammation or irritation of the mucous membranes in the mouth)
  • Loss of appetite
  • Weakness
  • Cough

Serious but rare side effects that have been seen with one or more of the EGFR inhibitors are:23,24,25,26,27

  • Breathing problems because of interstitial lung diseaseA group of disorders that cause scarring of the lungs, which eventually affects patients' ability to get enough oxygen into their bloodstream and to breathe
  • Liver and kidney damage
  • Eye inflammation
  • Severe skin lesions
  • Bleeding problems
  • Heart issues

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, together wtih, or after other treatments, which can include 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.3,28,29,30,31,32

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

There is currently one tyrosine kinase inhibitor that has been approved for patients with metastatic NSCLC whose tumors are ROS1-positive as detected by an FDA-approved test. 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 the ROS1 inhibitor work?

Crizotinib (Xalkori®) 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.20

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 (Xalkori®) on patients who are ROS1-positive are in general the same as those of patients who are ALK-positive. The most common side effects are:15,32

  • Visual problems
  • Diarrhea
  • Nausea
  • Swelling of the hands and feet
  • Constipation
  • Vomiting
  • Liver damage (as shown by abnormal blood tests related to liver function)
  • Feeling tired
  • Changes in taste
  • Dizziness

Most of these side effects are mild and not permanent.

When you start on crizotinib (Xalkori®), 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 (Xalkori®) will be the only treatment a ROS1-positive patient receives. However, in most cases, crizotinib (Xalkori®) is used before, together with, or after other treatments, which can include chemotherapy, surgery, and/or radiation therapy.

BRAF V600E combination inhibitor

Mutations in the BRAF gene occur in 1%-3% of lung adenocarcinoma patients.7 Unlike other driver mutations in lung cancer, BRAF mutations are commonly seen in lung cancer patients who are current or former smokers. The V600E mutation is the most common mutation in the BRAF gene, but other mutations (called non-V600E mutations) can also occur.3,33

Approved BRAF combination inhibitor

There is currently one FDA-approved targeted treatment for patients with metastatic NSCLC with a BRAF V600E mutation as detected by an FDA-approved test. This is a combination treatment of a BRAF tyrosine kinase inhibitor, dabrafenib (Tafinlar®), with a MEK kinase inhibitor, trametinib (Mekinist®).34,35,36  These and other targeted therapies are also being tested for patients with non-V600E BRAF mutations in clinical trials.

HOW DOES the BRAF V600E TKI combination INHIBITOR WORK?

The combination inhibitor works by blocking the signals that the abnormal BRAF proteins send to cells to grow and divide uncontrollably. This stops the growth and spread of the cancer cells.20

HOW IS IT ADMINISTERED?

Dabrafenib (Tafinlar®) is given as a pill twice daily approximately 12 hours apart and at least 1 hour before or at least 2 hours after eating. Trametinib (Mekinist®) is also given as a pill, but just once daily, at least 1 hour before or at least 2 hours after eating.35,36

WHAT ARE THE SIDE EFFECTS OF THE BRAF V600E combination INHIBITOR?

Like other targeted therapies, the combination of medications used to target BRAF V600E have a unique side-effect profile.34,35,36

Some common side effects of the BRAF V600E combination treatment include:35,36

  • Fever
  • Fatigue
  • Nausea
  • Vomiting
  • Diarrhea
  • Dry skin
  • Decreased appetite

Some rare but serious side effects of the combination inhibitor include cutaneous squamous cell carcinomas, non-cutaneous malignancies, hemorrhagic events, colitis, gastrointestinal performation, deep vein thrombosis, and pulmonary embolism.34,35,36

When you start on the combination therapy, 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.

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

Currently clinical trials are open for many drugs that inhibit the effect of mutations seen in NSCLC and small cell lung cancer. The targeted treatments are being studied alone, as well as in combination with other targeted agents, immunotherapy, chemotherapy, and radiation therapy. As the number of known driver mutations in lung cancer tumors increases, so does the number of drugs being developed to target them. Discuss with your doctor whether participating in a clinical trial might be a good option for you. Drugs that are currently being studied are intended to act against the following driver mutations:37

Driver Mutation Lung Adenocarcinoma Squamous Cell Lung Cancer Small Cell Lung Cancer
TP53 X X X
EGFR X    
KRAS X    
MEK1 (MAP2K1) X X  
RB1 X X X
ALK (fusion) X    
MYC X Rare X
FGFR1 (amp) X X X
RET X    
MET      
    Amplification (de novo) X    
    Amplification (EGFR TKI-resistant) X    
    Exon 14 skipping X X  
PTEN X X X
PIK3CA      
    Mutation X X  
    Amplification X X X
BRAF X    
ROS1 X    
NTRK1 X    
HER2      
    Mutation X    
    Amplification X    
IGR1     X
PARP1   X X
Notch signaling     X

Resistance to tyrosine kinase inhibitors (TKIs)

The biggest challenge of TKIs is that a majority of patients with lung cancer who initially benefit from them eventually develop resistance. Acquired resistanceDisease progression after a complete or partial response to treatment, or disease progression after 6 months or more of stable disease, after treatment with a targeted therapy is defined* as disease progression in a patient after:38,39

  • a complete or partial response following teatment with a targeted therapy OR
  • more than 6 months of stable disease following treatment with a targeted therapy

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

Cancer cells are clever enough to bypass roadblocks to their survival and often further mutate to overcome the effects of targeted drugs.

For example, the most common way adenocarcinomas become resistant to EGFR inhibitors is by mutating to a drug-resistant state that stops the drugs from working. Another way a tumor can become resistant to EGFR inhibitors is by activating a different signaling pathwayDescribes a group of molecules in a cell that work together to control one or more cell functions, such as cell division or cell death. After the first molecule in a pathway receives a signal, it activates another molecule. This process is repeated until the last molecule is activated and the cell function is carried out. Abnormal activation of signaling pathways can lead to cancer, and drugs are being developed to block these pathways. These drugs may help block cancer cell growth and kill cancer cells in the cell to bypass the pathway that the drug uses to kill the cells.38 In a small number of cases, the adenocarcinoma may transform into small cell lung cancer.40

Similarly, lung cancers with an ALK or ROS1 rearrangement normally have good responses to ALK or ROS1 inhibitors. However, the majority of patients also eventually become resistant to the effects of the drugs. In many cases, resistance arises because of further mutations.

Doctors and scientists are working to overcome resistance in tumors and to keep the TKIs effective against cancer for longer periods of time. Their approaches include:41

  • Simultaneously prescribing multiple enzyme inhibitorsA type of targeted cancer therapy that works by blocking the signals an enzyme sends cancer cells to grow, 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.

If a patient’s cancer has grown after treatment with targeted therapy, a decision needs to be made about the next treatment option. Your doctor may recommend that a biopsy be done of one of the tumors that is growing to determine whether there is a new mutation. For example, for EGFR patients, if the (EGFR) T790M mutation is present (it is found in about two-thirds of patients who have this biopsy), your doctor may recommend the next-generation EGFR inhibitor, osimertinib (Tagrisso®) or a clinical trial.41

In addition to osimertinib (Tagrisso®) for EGFR patients, several other next-generation inhibitors have already been approved, including ceritinib (Zykadia®, alectinib (Alecensa®), and brigatinib (Alunbrig®) for ALK-positive NSCLC patients.16,17,18 Scientists are researching approaches to overcome resistance to crizotinib (Xalkori®) in ROS1-positive lung cancer and learning about acquired resistance in BRAF-positive lung cancers.

How does targeted therapy differ from other lung cancer treatments?

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.20

Finding a clinical trial that might be right for you

If you are considering participating in a clinical trial, start by asking your healthcare 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.

Resources to help you navigate your clinical trials search:

  • LUNGevity Clinical Trial Finder: https://clinicaltrials.lungevity.org
    • Find available clinical trials by type of lung cancer and geographic location
    • Also find information and links to the medical centers at which these clinical trials are taking place
  • EmergingMed: www.emergingmed.com/lcctal/home
    • 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 9:00am to 5:00pm ET at 877-769-4834
  • National Cancer Institute (NCI)www.cancer.gov/clinicaltrials/search
  • My Cancer Genomewww.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 advanced (stage IIIB or IV) non-small cell lung cancer 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

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.

Learn more about clinical trials here.

Biomarker testing

To find out whether targeted therapy is appropriate for a person who has been diagnosed with lung cancer, that person's tumor tissue will be tested for the presence of driver mutations. Patients who have a mutation that a specific FDA-approved targeted therapy targets are candidates for that treatment. The process of testing for a mutation in a tumor is called biomarker testing (also know as mutation, genomic, or molecular testing). 

Note: At this time, tissue biopsies are the only way to confirm a diagnosis of lung cancer and to detect driver mutations. However, liquid biopsies, which make use of blood, can sometimes be used to look for resistance mutations like (EGFR) T790M and are being studied in other contexts.42,43

Biomarker Testing brochureTo help you understand and share this information, you can request our free booklet that summarizes the detailed information presented here.

Biomarker testing should be an ongoing part of the discussion with your doctors. Any decision to test for biomarkers should be made together, and will depend on a number of factors, including your type and stageThe extent of cancer in the body of lung cancer, your current treatment plan, your overall health, and your preferences.

Note that biomarker testing may also be used to determine whether an immunotherapy drug is appropriate. In this section, however, we are only discussing biomarker testing that will help doctors determine whether a targeted therapy is an appropriate treatment.

How is biomarker testing performed?

Once the decision has been made to do biomarker testing, a surgeon will remove either the entire tumor (surgery) of part of a tumor (biopsy). Be sure to confirm with your doctor that adequate tissue will be gathered so that all necessary biomarker tests can be performed.

There are a number of tissue collection techniques, including bronchoscopyA procedure that uses a bronchoscope to examine the inside of the trachea, bronchi, and lungs. A bronchoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue; this tissue can then be checked under a microscope for signs of disease. The bronchoscope is inserted through the nose or mouth, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)A type of bronchoscopy that uses a flexible bronchoscope fitted with an ultrasound device. Ultrasound uses high-frequency sound waves to make pictures of the insides of the body. The flexible tube is moved around to get a clear picture of the lung tissue. The picture is viewed on a computer screen to decide the optimal position for a biopsy, transthoracic needle biopsyA technique to biopsy cerain lung nodules and also some lymph nodes. This test is also called a percutaneous needle biopsy. A very thin needle is inserted through the chest wall to get a tissue sample, thoracoscopyThe examination of the inside of the chest, using a thorcoscope. A thoracoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue to be checked under a microscope for signs of disease, and thoracentesisA procedure that removes fluid that may build up around your lung. A needle is inserted through the skin into the lung and fluid is removed.42 Tumor tissue is then sent to a laboratory that can test it for driver mutations. Test results are generally available within 10 to 14 days. Biomarker testing can be done on both primary tumorsA term used to describe the original, or first, tumor in the body and metastatic tumors.43,44

Multiplex testing—testing for multiple gene mutations at the same time from the same sample of tumor tissue—is currently used in some laboratories. This allows more testing to be done on a small tumor sample. An example of multiplex testing is next-generation sequencing, or NGS.45

Who should have their tumor tested, and when?

Again, the decision to have your tumor tested and when depends on a number of factors. Below are common recommendations for biomarker tesing for driver mutations.42,43,44,46

Type of Lung Cancer Stage of Lung Cancer

Recommendations for Biomarker Testing for Driver Mutations

Adenocarcinoma Stage I, II, or III

Testing for the ALK, EGFR, KRAS, ROS1, and BRAF V600E mutations at the time of diagnosis

Stage IV or adenocarcinoma that has recurred or progressed after an initial diagnosis of stage I, II, or III in patients who were not previously tested

Tumors should be tested for ALK, EGFR, KRAS, ROS1, and BRAF V600E mutations at the time of diagnosis. Testing for other biomarkers may be helpful in deciding eligibility for clinical trials

While there is no approved targeted therapy for the KRAS driver mutations, testing for it can be informative because cancers with KRAS mutations are very unlikely to have other driver mutations. Targeted therapies for KRAS-positive cancers are being developed in clinical trials. Additionally, KRAS mutations can be associated with resistance to EGFR targeted therapy

Squamous cell lung cancer Stage I, II, or III

Currently, biomarker testing is performed only for clinical trials

Stage IV

If your doctors suspect that the tumor may have adenocarcinoma cells (this type of lung cancer is referred to as mixed lung cancer with an adenocarcinoma component), testing for ALK and EGFR mutarions is recommended. Otherwise, biomarker testing is currently only performed for clinical trials.

Small cell lung cancer All stages

Currently, biomarker testing is performed only for clinical trials

Testing to identify other possible mutations in the tumor may help you find clinical trials. These trials are testing new treatments for mutations in other types of lung cancer. Therefore, you should consider biomarker testing for other mutations if tests for ALK, EGFR, ROS1, or BRAF mutations are negative.

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

  • Before getting biomarker testing:

  • What are you trying to find with biomarker tests?
  • Have I already had any biomarker tests? Which ones?
  • Who performs these tests?
  • How are the tests performed?
  • Are there any complications from these tests?
  • How long will it take to get the test results?
  • Where can I get more information about biomarker testing?
  • Are there any limitations of biomarker testing?
  • Will insurance pay for these tests?
    After getting biomarker testing:
  • What tests were done?
  • What are the results of these tests?
  • How will the results affect my treatment?
  • The test results are negative: should I be retested?
  • The test results are not clear: should I be retested?
  • Are there any medications that target my type of lung cancer?
  • Will I need these tests again? If so, why? When?
  • Are there any clinical trials open to me based on these results?
  • How can I get a copy of my pathology report?

Questions to ask your healthcare 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 5, 2018


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