Targeted Therapy for Lung Cancer

myTomorrows Team 4 Oct 2022

8 mins read

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Patients with non-small cell lung cancer (NSCLC) may benefit from targeted therapy which inhibits malfunctioning genes and proteins that drive cancer growth. Targeted therapy attacks cancer cells that have certain biomarkers and usually do not damage healthy cells, unlike chemotherapy or radiation therapy.

Patients with non-small cell lung cancer (NSCLC) may benefit from targeted therapy, which targets malfunctioning proteins on the surface or inside of their cancer cells. Cancer cells gain the ability to grow and spread uncontrollably by acquiring mutations in genes. Each gene encodes, or is a set of instructions for, a protein. Gene mutations that drive cells to become cancerous usually impair proteins that function to control cell growth, cell movement, and cell survival. Targeted drug therapies are available to target impaired proteins in lung cancer.

Patients with NSCLC may be recommended targeted therapy when their cancer cannot be removed with surgery due to spreading to the lymph nodes, when their cancer recurs after or does not respond to chemotherapy, or when it has metastasized to other parts of the body. At the time of writing, there are no targeted therapies available for small-cell lung cancer.

Targeted therapies mainly target driver mutations, which are mutations that transform a normal cell into a cancer cell. Cancer cells need the driver mutation to survive and grow. Driver mutations that can be matched to appropriate targeted therapies are identified through biomarker testing or genotyping of tumor samples. Identification of driver mutations and the use of appropriate targeted therapies have been shown to extend survival in lung cancer patients.

Cancer cells are prone to developing mutations and not all mutations are driver mutations. As opposed to driver mutations, passenger mutations are less essential to cancer growth and survival. Some passenger mutations can be targeted by drugs.

The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association of Molecular Pathologists recommend that patients with adenocarcinoma histology or who have light- or never-smoking history have testing for mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes. Rapid and sensitive tests are available to test these genes for common mutations that are targetable by drugs.

Approximately 15 percent of NSCLC adenocarcinomas in the US have mutations in EGFR. The incidence of EGFR mutation is 62 percent in Asian populations. Mutations involving ALK are found in about 4 percent of NSCLC adenocarcinomas in the US. Targeted therapy is the recommended first line of treatment for NSCLC patients who have mutations in EGFR or ALK.

Targeted therapies are also available for NSCLC tumors that have mutations involving the genes ROS1, KRAS, BRAF, NTRK, NRG1, MET, RET, and HER2. Mutations in these genes cause the proteins they encode to malfunction in their role as a cell growth signal, resulting in too much cell growth. Targeted therapies have been developed to block or inhibit the activity of these malfunctioning proteins to bring cell growth back under control. FDA-approved first-line treatments for NSCLC are targeted against ROS1, BRAF, MET, RET, and NTRK mutations.

EGFR-positive NSCLC

If tumor biomarker testing finds EGFR-positive (EGFR +) cancer, this means that the gene that encodes the protein called epidermal growth factor receptor (EGFR) is mutated. EGFR is a tyrosine kinase type of protein. Tyrosine kinase proteins function like an on/off switch and tyrosine kinase inhibitor (TKI) drugs inhibit these types of proteins. EGFR is located on the cell surface and its tyrosine kinase switch normally controls cell division. Different mutations cause the EGFR switch to be stuck in the on position which causes more cell division than normal. EGFR tyrosine kinase inhibitors (EGFR TKIs) are a category of targeted therapy that blocks EGFR and prevents it from telling the cells to keep dividing. There are several EGFR TKI drugs available. Treatment choice and timing are guided by patient circumstances and protocol.

ALK-positive NSCLC

Anaplastic lymphoma kinase (ALK) is a gene that is sometimes mutated in NSCLC, causing the ALK tyrosine kinase protein to malfunction. ALK-positive (ALK +) mutations cause cancer to grow and spread. There are several ALK TKIs with varying indications. Some may be indicated for use if resistance to another ALK TKI targeted therapy develops.

ROS1-positive NSCLC

Approximately 1-2 percent of NSCLCs have ROS1 rearrangements in which part of the C-ROS oncogene 1 (ROS1) receptor tyrosine kinase gene is abnormally joined to another gene. These rearrangements cause ROS1 to be stuck in the on position, promoting cell growth. Depending on the stage of their disease, patients with ROS1-positive NSCLC may be treated with ROS1 inhibitors as per guidelines.

BRAF-positive NSCLC

The BRAF gene encodes a serine/threonine kinase protein that acts as a control switch for cell growth. BRAF mutations are usually associated with a history of smoking and are found in about 1 to 3 percent of NSCLCs.

When the location of the BRAF mutation is at V600E, a two-drug combination targeted therapy may be recommended. One drug is a BRAF inhibitor and the other inhibits the MEK protein, which receives signals from BRAF to control cell division. For NSCLC cases that have a BRAF mutation outside of the V600E site (BRAF non-V600E), other treatment strategies such as a different MEK inhibitor may be used.

MET mutations in NSCLC

METex14 is a mutation in the MET gene which encodes c-MET, a tyrosine kinase protein. METex14 is found in 3 percent of lung adenocarcinomas. METex14 causes the MET protein, normally a short-lived signal for cell growth, to avoid getting broken down inside the cell. By avoiding this degradation process, METex14 causes MET to signal cell growth for a longer period of time.

MET amplification is another type of MET mutation where there are extra copies of the gene, resulting in more than normal amounts of cell growth signal. MET inhibitors may be used as first-line treatment or subsequent-line treatment for NSCLC with METex14 and as a later-line option for MET amplification in advanced NSCLC.

RET fusion-positive NSCLC

The RET gene codes for a tyrosine kinase protein. RET inhibitor drugs may be used to treat NSCLC when RET is fused to another gene. RET fusion proteins are overactive, signaling too much cell growth and division. Genetic rearrangements involving RET occur in 1 to 2 percent of adenocarcinoma-type cancers.

KRAS mutations in NSCLC

KRAS mutations that activate the KRAS protein are found in 20 to 25 percent of lung adenocarcinomas in the US and these mutations are generally associated with smoking. Targeted therapy is available for the G12C mutation in the KRAS gene.

NTRK fusion-positive NSCLC

NTRK (neurotrophic receptor tyrosine kinase) gene fusions, in which the NTRK gene is attached to another gene, occur in less than 1 percent of NSCLC cases. Tyrosine receptor kinase (TRK) inhibitor drugs are targeted therapy drugs that may be used for patients with advanced, NTRK-positive NSCLC.

NRG1-fusion NSCLC

Gene fusions involving neuregulin 1 (NRG1) occur in less than 1 percent of NSCLC cases. NRG1 controls cell growth by binding to tyrosine kinase receptors. Research suggests that NRG1-fusion cancers respond poorly to chemotherapy and immunotherapy. Targeted therapeutics against NRG1 fusions are currently under investigation in clinical trials.

HER2 mutations in NSCLC

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor protein that regulates cell growth. Mutations in the HER2 gene are found in approximately 1 to 3 percent of NSCLC tumors, predominantly in adenocarcinomas. HER2 mutations have a higher prevalence in never-smokers and women. Clinical trials for anti-HER2 therapy are ongoing.

Angiogenesis inhibitors

Angiogenesis inhibitors are targeted therapies that inhibit proteins that promote the development of new blood vessels, a process called angiogenesis. Angiogenesis allows tumors to receive nutrients and oxygen. Angiogenesis inhibitors aim to stop the development of new blood vessels to starve the tumor. Vascular endothelial growth factor (VEGF), a protein that helps new blood vessels form, is the target of one angiogenesis inhibitor. Angiogenesis inhibitor drugs may be given along with chemotherapy.

Targeted therapy side effects

Since targeted therapy attacks cancer cells that have certain biomarkers, it usually does not damage healthy cells. This means that there are potentially fewer and less severe systemic side effects with targeted therapy. Any type of treatment for NSCLC can cause side effects and each person’s experience with side effects is different.

Side effects for targeted therapy mainly depend on the type of drug or the combination of drugs, how they are given, and the overall health of the individual. All targeted therapies for NSCLC can produce flu-like symptoms, fatigue, diarrhea, constipation, low white blood cell count, loss of appetite, taste changes, nausea, weight gain, difficulty breathing, cough, eye problems, and skin problems.

EGFR inhibitors (EGFR TKIs) may cause sore mouth, headache, and sleep problems. ALK inhibitors (ALK TKIs) may cause stomach pain and cramping, heartburn, indigestion, peripheral nerve damage, blood clots, and anemia. Some additional side effects are possible with specific types of targeted therapies. Immunotherapy can increase the toxicity of TKIs given in a later course of treatment. Treatment choice and potential side effects should always be discussed with your treating physician.

Targeted therapies are treatments that inhibit malfunctioning genes and proteins that drive cancer growth. Patients with NSCLC, particularly those with adenocarcinoma and a light- or never-smoking history, may benefit from targeted therapy. Targeted therapies are personalized to the patient and mutations that have arisen in their cancer.

myTomorrows is dedicated to helping patients with lung cancer find and access lung cancer clinical trials and other potential treatment options.

The information in this blog is not intended as a substitute for a medical consultation. Always consult a doctor before receiving a diagnosis or treatment.

The myTomorrows team
Anthony Fokkerweg 61-2
1059CP Amsterdam
The Netherlands

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KnowledgeLung CancerTargeted TherapiesNSCLC

myTomorrows Team 4 Oct 2022

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