Targeted Therapy for Non-Small Cell Lung Cancer

As researchers have learned more about the changes in non-small cell lung cancer (NSCLC) cells that help them grow, they have developed drugs to specifically target these changes. Targeted drugs work differently from standard chemotherapy (chemo) drugs. They sometimes work when chemo drugs don’t, and they often have different side effects. At this time, targeted drugs are most often used for advanced lung cancers, either along with chemo or by themselves.

Drugs that target tumor blood vessel growth (angiogenesis)

For tumors to grow, they need to form new blood vessels to keep them nourished. This process is called angiogenesis. Some targeted drugs, called angiogenesis inhibitors, block this new blood vessel growth:

  • Bevacizumab (Avastin) is used to treat advanced NSCLC. It is a monoclonal antibody (a man-made version of a specific immune system protein) that targets vascular endothelial growth factor (VEGF), a protein that helps new blood vessels to form. This drug is often used with chemo for a time. Then if the cancer responds, the chemo may be stopped and bevacizumab is given by itself until the cancer starts growing again.
  • Ramucirumab (Cyramza) can also be used to treat advanced NSCLC. This drug is a monoclonal antibody that targets a VEGF receptor (protein). It helps stop the formation of new blood vessels. This drug is often combined with chemo and most often given after another treatment stops working.

Side effects of angiogenesis inhibitors

Common side effects of these drugs include:

Rare but possibly serious side effects can include blood clots, severe bleeding, holes (called perforations) in the intestine, heart problems, and slow wound healing. If a hole forms in the intestine it can lead to severe infection and may require surgery to fix.

Because of the risks of bleeding, these drugs typically aren’t used in people who are coughing up blood or who are taking drugs called blood thinners. The risk of serious bleeding in the lungs is higher in patients with the squamous cell type of NSCLC, which is why current guidelines do not recommend using bevacizumab in people with this type of lung cancer.

Drugs that target cells with EGFR gene changes

Epidermal growth factor receptor (EGFR) is a protein on the surface of cells. It normally helps the cells grow and divide. Some NSCLC cells have too much EGFR, which makes them grow faster. Drugs called EGFR inhibitors can block the signal from EGFR that tells the cells to grow. Some of these drugs can be used to treat advanced NSCLC.

EGFR inhibitors used in NSCLC with EGFR gene mutations

  • Erlotinib (Tarceva)
  • Afatinib (Gilotrif)
  • Gefitinib (Iressa)
  • Osimertinib (Tagrisso)
  • Dacomitinib (Vizimpro)

These drugs can be used alone (without chemo) as the first treatment for advanced NSCLCs that have certain mutations in the EGFR gene. These gene mutations are more common in women, Asians, and people who haven’t smoked (or light smokers). Erlotinib can also be used for advanced NSCLC without these mutations if chemo isn’t working. All of these medicines are taken as pills.

EGFR inhibitors that target cells with the T790M mutation

EGFR inhibitors can often shrink tumors for several months or more. But eventually these drugs stop working for most people, usually because the cancer cells develop another mutation in the EGFR gene. One such mutation is known as T790M. Osimertinib (Tagrisso) is an EGFR inhibitor that works against cells with the T790M mutation.

Doctors now commonly get another biopsy when EGFR inhibitors have stopped working to see if the patient's tumor has developed the T790M mutation.

EGFR inhibitors used for squamous cell NSCLC

Necitumumab (Portrazza) is a monoclonal antibody (a man-made version of an immune system protein) that targets EGFR. It can be used with chemotherapy as the first treatment in people with advanced squamous cell NSCLC. This drug is given as an infusion into a vein (IV).

Side effects of EGFR inhibitors

Common side effects of all EGFR inhibitors include:

  • Skin problems
  • Diarrhea
  • Mouth sores
  • Loss of appetite

Skin problems can include an acne-like rash on the face and chest, which in some cases can lead to skin infections. For more detailed information on the skin problems that can result from anti-EGFR drugs, see Targeted Therapy.

These drugs can also cause more serious, but less common, side effects. For example, necitumumab can lower the levels of certain minerals in the blood, which can affect the heart rhythm and in some cases might be life-threatening.

Drugs that target cells with ALK gene changes

About 5% of NSCLCs have a rearrangement in a gene called ALK. This change is often seen in non-smokers (or light smokers) who are younger and who have the adenocarcinoma subtype of NSCLC. The ALK gene rearrangement produces an abnormal ALK protein that causes the cells to grow and spread. Drugs that target the abnormal ALK protein include:

  • Crizotinib (Xalkori)
  • Ceritinib (Zykadia)
  • Alectinib (Alecensa)
  • Brigatinib (Alunbrig)
  • Lorlatinib (Lorbrena)

These drugs can often shrink tumors in people whose advanced lung cancers have an ALK gene change. Although they can help after chemo has stopped working, they are often used instead of chemo in people whose cancers have an ALK gene rearrangement.

These drugs are taken as pills.

Side effects of ALK inhibitors

Common side effects of ALK inhibitors include:

Other side effects are also possible with some of these drugs. Some side effects can be severe, such as inflammation (swelling) in the lungs or other parts of the body, liver damage, nerve damage (peripheral neuropathy), and heart rhythm problems.

Drugs that target cells with ROS1 gene changes

About 1% to 2% of NSCLCs have a rearrangement in a gene called ROS1. This change is most often seen in people who have the adenocarcinoma subtype of NSCLC and whose tumors are also negative for ALK, KRAS and EGFR mutations. The ROS1 gene rearrangement is similar to the ALK gene rearrangement, and some drugs can work on cells with either ALK or ROS1 gene changes. Drugs that target the abnormal ROS1 protein include:

  • Crizotinib (Xalkori)
  • Ceritinib (Zykadia)
  • Lorlatinib (Lorbrena)
  • Entrectinib (Rozlytrek)

These drugs can often shrink tumors in people whose advanced lung cancers have a ROS1 gene change. Crizotinib or ceritinib might be used as first treatment, instead of chemo, and lorlatinib may be used when crizotinib or ceritinib have stopped working. Entrectinib can be used in people with metastatic NSCLC that has a ROS1 gene change.

These drugs are taken as pills.

Side effects of drugs that target cells with ROS1 gene changes

Common side effects of ROS1 inhibitors include:

  • Dizziness
  • Diarrhea
  • Constipation
  • Fatigue
  • Changes in vision

Other side effects are also possible with some of these drugs. Some side effects can be severe, sush as inflammation (swelling) in the lungs or other parts of the body, liver damage, nerve damage (peripheral neuropathy), and heart problems.

Drugs that target cells with BRAF gene changes

In some NSCLCs, the cells have changes in the BRAF gene. Cells with these changes make an altered BRAF protein that helps them grow. Some drugs target this and related proteins:

  • Dabrafenib (Tafinlar) is a type of drug known as a BRAF inhibitor, which attacks the BRAF protein directly.
  • Trametinib (Mekinist) is known as a MEK inhibitor, because it attacks the related MEK proteins. 

These drugs can be used together to treat metastatic NSCLC if it has a certain type of BRAF gene change. 

These drugs are taken as pills or capsules each day.

Side effects of drugs that target cells with BRAF gene changes

Common side effects can include skin thickening, rash, itching, sensitivity to the sun, headache, fever, joint pain, fatigue, hair loss, nausea, and diarrhea.

Less common but serious side effects can include bleeding, heart rhythm problems, liver or kidney problems, lung problems, severe allergic reactions, severe skin or eye problems, and increased blood sugar levels.

Some people treated with these drugs develop skin cancers, especially squamous cell skin cancers. Your doctor will want to check your skin often during treatment and for several months after. You should also let your doctor know right away if you notice any new growths or abnormal areas on your skin.

Drugs that target cells with NTRK gene changes

A very small number of NSCLCs have changes in one of the NTRK genes. Cells with these gene changes can lead to abnormal cell growth and cancer. Larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) target and disable the proteins made by the NTRK genes. These drugs can be used in people with advanced lung cancer that is still growing depsite other treatments and whose tumor has an NTRK gene change.

These drugs are taken as pills, once or twice daily.

Side effects of drugs that target cells with NTRK gene changes

Common side effects include dizziness, fatigue, nausea, vomiting, constipation, weight gain, and diarrhea.

Less common but serious side effects can include abnormal liver tests, heart problems, and confusion.

To learn more about some of the side effects listed here and how to manage them, see Managing Cancer-related Side Effects.

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing.

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Last Medical Review: October 1, 2019 Last Revised: October 1, 2019

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