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Targeted Drug 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.

When is targeted therapy used?

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.

Angiogenesis inhibitors

How they work (mechanism of action): For tumors to grow, they need to form new blood vessels to keep them nourished. This process is called angiogenesis. Angiogenesis inhibitors help stop the formation of new blood vessels. These inhibitors are generally monoclonal antibodies (lab-made versions of a specific immune system protein) that target vascular the endothelial growth factor (VEGF), a protein that helps new blood vessels to form, called VEGF inhibitors.

Examples of VEGF inhibitors:

  • Bevacizumab (Avastin) is used in combination with chemotherapy, immunotherapy, or the targeted drug erlotinib for management of advanced or metastatic NSCLC.
  • Ramucirumab (Cyramza) is used in combination with the targeted drug erlotinib or chemotherapy for management of advanced or metastatic NSCLC.

Side effects of angiogenesis inhibitors:

  • Common side effects: Nosebleed, headache, high blood pressure, protein in urine, change in taste, dry skin, back pain, dry skin, excessive tearing
  • Rare, but serious side effects: Severe bleeding, formation of holes (perforations) in the intestine, issues with wound healing, clots in the heart and/or brain, brain damage called reversible posterior leukoencephalopathy syndrome (RPLS), very high blood pressure, kidney damage, allergic reaction to the drug (infusion reaction), thyroid damage, ovarian failure, fetal harm

Because of the risks of bleeding, these drugs often 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.

KRAS inhibitors

How they work (mechanism of action): In some NSCLCs, the cancer cells have changes in the KRAS gene that cause them to make an abnormal form of the KRAS protein. This abnormal protein helps the cancer cells grow and spread. About 1 in 8 people with NSCLC have a specific type of KRAS gene change called a KRAS G12C mutation. KRAS inhibitors attach to the KRAS G12C protein, which helps keep cancer cells from growing.

These drugs are taken as pills, typically once or twice a day.

NSCLCs with this mutation are often resistant to other targeted drugs, such as EGFR inhibitors (see below).

Examples of KRAS inhibitors:

  • Sotorasib (Lumakras) is used alone for advanced NSCLC with the KRAS G12C mutation if you’ve already had at least one other type of drug treatment.
  • Adagrasib (Krazati) can be used in ways similar to sotorasib.

Side effects of KRAS inhibitors:

  • Common side effects: Diarrhea, nausea and vomiting, muscle pain, fatigue, cough, decreased white blood cell and red blood cell counts, changes in other blood tests
  • Rare, but serious side effects: Kidney damage, liver damage, lung damage called interstitial lung disease (ILD)/ pneumonitis, a heart condition called QTc interval prolongation (see below).

EGFR inhibitors

How they work (mechanism of action): Epidermal growth factor receptor (EGFR) is a protein on the surface of cells. It normally helps the cells grow and divide. Sometimes NSCLC cells have too much EGFR, which makes them grow faster. Drugs called EGFR inhibitors can block the signal from EGFR that tells the cancer cells to grow. Some of these drugs are often used to treat advanced NSCLCs that have certain mutations in the EGFR gene, although osimertinib can also be used as an adjuvant (additional) treatment after surgery for some earlier-stage lung cancers.

Examples of EGFR inhibitors:

  • EGFR inhibitors that target cells with either an exon 19 or exon 21 mutation: Osimertinib (Tagrisso) is often the preferred first treatment for advanced NSCLC with these mutation(s). Afatinib (Gilotrif), erlotinib (Tarceva), dacomitinib (Vizimpro), gefitinib (Iressa), or erlotinib in combination with a VEGF inhibitor (see above) are also options.
  • EGFR inhibitors that target cells with S768I, L861Q and/or G719X mutations: Afatinib (Gilotrif) or osimertinib (Tagrisso) is often the preferred first treatment for advanced NSCLC with these mutation(s). Erlotinib (Tarceva), dacomitinib (Vizimpro), and gefitinib (Iressa) are options as well.
  • EGFR inhibitors that target cells with an exon 20 mutation: Amivantamab (Rybrevant) is a monoclonal antibody (a lab-made version of a specific immune system protein) that targets two proteins that help cancer cells grow: EGFR and MET. Because it binds to two proteins, it’s called a bispecific antibody. It is usually given after chemotherapy has been tried.

Side effects of EGFR inhibitors:

  • Common side effects: Skin problems, nail changes, fatigue, loss of appetite, nausea, vomiting, diarrhea
  • Rare, but serious side effects: A lung condition called interstitial lung disease (ILD)/ pneumonitis; damage to the heart muscle; heart rhythm changes; other organ damage including kidney, gut and liver; harm to a fetus; severe skin rashes

ALK inhibitors

How they work (mechanism of action): About 5% of NSCLCs have a rearrangement in a gene called ALK. This change is often seen in people who don’t smoke (or who are 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 inhibit this ALK protein are called ALK inhibitors and are taken as an oral pill.

Examples of ALK inhibitors:

  • Second-generation ALK inhibitors: Alectinib (Alecensa), brigatinib (Alunbrig), lorlatinib (Lorbrena), and ceritinib (Zykadia) are second-generation ALK inhibitors and can get into the brain better than crizotinib, a first-generation ALK inhibitor. They are often the preferred first treatment for advanced NSCLC with the ALK rearrangement mutation. Studies are also looking at offering these drugs in the adjuvant setting (after a lung tumor has been removed) for early-stage NSCLC. 
  • First- generation ALK inhibitor: Crizotinib (Xalkori) was the first ALK inhibitor approved for advanced NSCLC with an ALK rearrangement. It is still given in certain situations.

Side effects of ALK inhibitors:

  • Common side effects: Vision changes, nausea, vomiting, diarrhea, swelling in hands and/or feet, tiredness, muscle soreness, nerve damage (peripheral neuropathy), changes in lab values
  • Rare, but serious side effects: Liver damage; a lung condition called interstitial lung disease (ILD)/pneumonitis; changes in heart rhythm; harm to a fetus

ROS1 inhibitors

How they work (mechanism of action): 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. These drugs, called ROS1 inhibitors, can often shrink tumors in people whose advanced lung cancers have a ROS1 gene change. They are taken as a pill.

Examples of ROS1 inhibitors:

  • Entrectinib (Rozlytrek), crizotinib (Xalkori),and ceritinib (Zykadia) are often the first treatment options for advanced NSCLC with a ROS1 rearrangement.
  • Lorlatinib (Lorbrena) is an option for patients with ROS1-mutated advanced NSCLC who have already been treated with the either entrectinib, crizotinib, or ceritinib.  
  • Repotrectinib (Augtyro) is an option for patients with ROS1-mutated advanced NSCLC who have or who have not been treated with a ROS1 inhibitor.

Side effects of ROS1 inhibitors:

  • Common side effects: Vision changes, muscle soreness, swelling in hands and/or feet, nerve damage (called peripheral neuropathy), diarrhea, fatigue, changes in lab tests
  • Rare, but serious side effects: Liver damage; changes in heart rhythm and heart function; lung condition called interstitial lung disease (ILD)/pneumonitis; high blood pressure; changes in mood or mental status; harm to a fetus

BRAF inhibitors

How they work (mechanism of action): 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.

These drugs are taken as pills or capsules each day.

Examples of BRAF inhibitors:

  • Combination treatment: A combination of BRAF inhibitor and a MEK inhibitor is often given together as the first or later treatment for advanced NSCLC with the BRAF V600E mutation. Examples include:
  • Dabrafenib (Tafinlar), a BRAF inhibitor, with trametinib (Mekinist), a MEK inhibitor
  • Encorafenib (Braftovi), a BRAF inhibitor, with binimetinib (Mektovi), a MEK inhibitor
  • Single drug treatment: Vemurafenib (Zelboraf), another BRAF inhibitor, or dabrafenib can be taken alone if the patient can’t take the combination treatment.

Side effects of BRAF inhibitors:

  • Common side effects: Skin thickening, rash, itching, sensitivity to the sun, headache, fever, joint pain, tiredness, hair loss, nausea, diarrhea
  • Rare, but serious side effects: Bleeding, heart rhythm problems, liver or kidney problems, lung problems, severe allergic reactions, severe skin or eye problems, increased blood sugar levels, squamous cell skin cancer

RET inhibitors

How they work (mechanism of action): In a small percentage of NSCLCs, the tumor cells have rearrangement in the RET gene that cause them to make an abnormal form of the RET protein. This abnormal protein helps the tumor cells grow.  Drugs known as RET inhibitors can be used to treat advanced NSCLC with the RET rearrangement.

These drugs are taken by mouth as capsules, typically once or twice a day.

Examples of RET inhibitors:

  • Selpercatinib (Retevmo) or pralsetinib (Gayreto) is often the preferred first treatment for metastatic NSCLC with the RET rearrangement.
  • Cabozantinib (Cometriq, Cabometyx) has activity against RET, ROS1, MET, and VEGF. It can be used to treat RET-mutated NSCLC in certain situations.

Side effects of RET inhibitors:

  • Common side effects: Dry mouth, diarrhea or constipation, high blood pressure, tiredness, swelling in hands and/or feet, skin rash, muscle and joint pain, low blood cell counts or changes in other blood tests
  • Rare, but serious side effects: Liver damage, lung damage, allergic reactions, changes in heart rhythm, bleeding easily, and problems with wound healing

MET inhibitors

How they work (mechanism of action): In some NSCLCs, cancer cells have changes in the MET gene, called a MET exon 14 skipping mutation, that cause them to make an abnormal form of the MET protein. This abnormal protein helps the cancer cells grow and spread. Drugs called MET inhibitors can be used to treat metastatic NSCLC if the cancer cells have certain types of MET gene changes, by attacking the MET protein. They are taken as a pill once or twice a day.

Examples of MET inhibitors:

  • Capmatinib (Tabrecta) or tepotinib (Tepmetko) is often the preferred first treatment for metastatic NSCLC with the MET exon 14 skipping mutation.
  • Crizotinib (Xalkori) has activity against MET, ALK, and ROS1. It can be used to treat MET-mutated NSCLC in certain situations. 

Side effects of MET inhibitors:

  • Common side effects: Nausea, vomiting, diarrhea, tiredness, swelling in hands and/or feet, muscle and joint pain, low blood cell counts, or changes in other blood tests
  • Rare, but serious side effects: A lung condition called interstitial lung disease (ILD)/pneumonitis; liver damage; harm to a fetus; increased sensitivity to sunlight (photosensitivity)

HER2-directed drugs

How they work (mechanism of action): In a small percentage of NSCLCs, the cancer cells have certain changes in the HER2 (ERBB2) gene that help them grow. HER2-directed drugs can be used to treat metastatic NSCLC if the cancer cells have certain types of HER2 gene changes. These drugs are infused into a vein (IV). They are typically given once every few weeks.

Examples of HER2 inhibitors:

  • Fam-trastuzumab deruxtecan-nxki (Enhertu) is an antibody-drug conjugate (ADC). It’s made up of a lab-made antibody that targets the HER2 protein, which is linked to a chemotherapy drug. The antibody acts like a homing signal by attaching to the HER2 protein on cancer cells, bringing the chemo directly to them. It can be used to treat NSCLC with HER2 mutations if you’ve already had at least one other type of drug treatment.
  • Ado-trastuzumab emtansine (Kadcyla) is also a HER2-targeted ADC. It can be used to treat HER2-mutated NSCLC in certain situations.

Side effects of HER2 inhibitors:

  • Common side effects: Low white blood cell, red blood cell, and platelet counts; tiredness; hair loss; nausea and vomiting; muscle and joint pain; changes in other blood tests
  • Rare, but serious side effects, specific to fam-trastuzumab deruxtecan: Changes in heart function; severely low white blood cell count, which increases your risk of infection

TRK inhibitors

How they work (mechanism of action): A very small number of NSCLCs have changes in one of the NTRK genes, called NTRK gene fusions. Cells with these gene changes make abnormal TRK proteins, which can lead to abnormal cell growth and cancer. TRK inhibitors target and disable the proteins made by the NTRK genes.

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

Examples of TRK inhibitors:

  • Larotrectinib (Vitrakyi) or entrectinib (Rozlytrek) is often the preferred first treatment for metastatic NSCLC with an NTRK gene fusion mutation.

Side effects of NTRK inhibitors:

  • Common side effects: Abnormal liver tests; decreased white blood cell and red blood cells; muscle and joint pain; tiredness; diarrhea or constipation; nausea and vomiting; stomach pain
  • Rare, but serious side effects: Mental changes, such as confusion, changes in mood, changes in sleep; liver damage; changes in heart rhythm and/or function; vision changes; harm to a fetus

More information about targeted therapy

To learn more about how targeted drugs are used to treat cancer, see Targeted Cancer Therapy.

To learn 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 Revised: November 22, 2023

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