Targeted Therapies for Lung Cancer

Today, there is a more personalized approach to treating non-small cell lung cancer (NSCLC) than ever before. With better understanding of genetic abnormalities (mutations) that initiate lung cancer cell growth and then drive the continual spread of cancer cells, researchers have been able to develop targeted therapies that act on specific genetic mutations to prevent lung cancer from growing, shrink tumors, or manage cancer symptoms.

Targeted therapy drugs for lung cancer have been available since 2011 and are used for advanced-stage lung cancer. For each of the known mutations for which there are targeted therapies, a specific drug or combination of treatments is prescribed to zero in on the precise issues related to that diagnosis—a treatment strategy known as precision medicine.

These mutations are most common in lung adenocarcinoma, occurring in an estimated 70% of people with that type of cancer.

EGFR Mutations

EGFR-positive lung cancer refers to lung cancers in which the epidermal growth factor receptor (EGFR) on some cancer cells is altered. When EGFR doesn't perform the way it should, it causes rapid cell growth that helps cancer spread.

The targeted therapy drugs prescribed for EGFR mutations and other genetic mutations include tyrosine kinase inhibitors. These prevent the protein on mutated cells from triggering tyrosine kinase, an enzyme within cells that activates cell division. By halting cell division, these drugs stop cancer cells from multiplying and spreading.

Drugs approved to treat EGFR mutations include:

• Tagrisso (osimertinib)
• Tarceva (erlotinib)
• Iressa (gefitinib)
• Rybrevant (amivantamab-vmjw) 

Tagrisso is usually recommended as the first treatment for EGFR because it can be effective in stopping lung cancer spread to the brain (metastases).

EGFR targeted therapy drugs offer higher response rates and longer progression-free survival rates compared to traditional chemotherapy.

ALK Rearrangements

ALK rearrangements refer to a fusion of two genes known as anaplastic lymphoma kinase (ALK) and EML4 (echinoderm microtubule-associated protein-like 4). This fusion produces abnormal ALK proteins in the cancer cells, which cause the cells to grow and spread.

Five drugs have been approved by the U.S. Food and Drug Administration (FDA) to target ALK rearrangement:

• Alecensa (alectinib)
• Alunbrig (brigatinib)
• Lorbrena (lorlatinib)
• Xalkori (crizotinib) 
• Zykadia (ceritinib)

ALK inhibitors are usually used instead of chemo in people who have tested positive for the mutation. However, in some patients, ALK inhibitors are only introduced after chemo has stopped working.

ROS1 Rearrangements

A ROS1 rearrangement is a fusion between ROS1 and another gene, which, like ALK rearrangement, results in an abnormal protein that causes cancer cells to multiply.

Currently, two oral medications have FDA approval for patients with metastatic NSCLC who have ROS1-positive lung cancer:

• Rozlytrek (entrectinib)
• Xalkori (crizotinib)

Other drugs are undergoing clinical trials, and there is hope that additional medications will be available in the near future.

MET Amplifications

Cancer cells in some NSCLC include a mutation of the MET (mesenchymal epithelial transition) gene that causes them to produce abnormal proteins that lead to tumors spreading.

The FDA has approved one drug that works to attack the MET protein and stop the cancer from spreading: Tabrecta (capmatinib).

Specifically, this drug is approved for adult NSCLC patients who have metastatic tumors with the MET gene changes. 

BRAF Mutations

Common in current or former smokers, BRAF mutations are acquired mutations that affect B-Raf proteins. The mutation results in continual cancer spread by:

• Promoting cell proliferation
• Promoting cell survival
• Aiding in cell maturation
• Aiding in the movement of cells
• Inhibiting natural cell death or self-destruction

There are variations of BRAF mutations, and non-V600E mutations are the most common in NSCLC, affecting around 50% to 80% of BRAF mutations in lung adenocarcinoma.

One FDA-approved targeted treatment stops this continual process: a combination treatment of the BRAF kinase inhibitor Tafinlar (dabrafenib) and a MEK kinase inhibitor Mekinist (trametinib).

KRAS Mutations

The KRAS gene is involved in regulating signaling pathways that manage cell growth and division. Mutations in this gene can, therefore, cause cells to proliferate in an uncontrolled way.

KRAS mutations make up about 25% of mutations in NSCLC, and for a long time they were considered resistant to drug therapy.

In 2021, the FDA approved Lumakras (sotorasib), a KRAS inhibitor, for the treatment of NSCLC in those with the KRAS G12C mutation and who have already received systemic therapy. In 2022, the FDA approved Krazati (adagrasib), the second targeted therapy for this mutation.

There are currently other drugs for KRAS-positive lung cancer that look promising in clinical trials.

NTRK Gene Fusion

NTRK gene fusion occurs when a piece of the chromosome containing an NTRK gene breaks off and fuses with a gene on another chromosome. This produces proteins called TRK fusion proteins, which cause abnormal cell growth and cancer.

This less-common mutation is most often found among non-smokers or light smokers.

Two drugs are approved to disable these proteins:

• Rozlytrek (entrectinib)
• Vitrakvi (larotrectinib)

These drugs are recommended when cancer is inoperable and no alternative treatment is available.

RET Fusion

A small percentage of NSCLC patients test positive for a mutation known as RET fusion, in which the RET gene on cancer cells changes and forms RET proteins that cause cell proliferation.

Retevmo (selpercatinib) has been approved to target these cells. This RET inhibitor attacks the RET protein to halt the growth of tumors.

Side Effects and Drug Resistance

Targeted therapy drugs are often praised because the side effects are significantly more mild than chemotherapy drugs. However, there is a risk of side effects. One of the most common problems is a skin rash that can vary from mild to severe.

Other common side effects include:

• Nausea and vomiting
• Diarrhea
• Constipation
• Fatigue

Targeted therapy has enabled many people with advanced lung cancer to manage their disease like any chronic illness, such as diabetes. However, control over lung cancer is likely to be temporary. Resistance to targeted therapies is very common. Your healthcare provider will prescribe a new treatment once you show signs of resistance, but that treatment might become ineffective as well.

Sometimes finding a new treatment means prescribing medications for off-label uses. For instance, Lorbrena is not approved for ROS1 rearrangement, but if resistance occurs to the approved drugs, your healthcare provider may recommend it. Check with your insurance to see if coverage is offered for off-label uses.

A Word From Verywell

Depending on your case, targeted therapies may be used alone or in combination with traditional chemotherapy.

Ask your healthcare provider about genetic testing and the above drug options, and look for clinical trials focused on treatments for your type of genetic mutation. There are constant studies being run that offer hope for new ways to manage cancer.