What is targeted therapy?
Targeted therapy is a cancer treatment that uses drugs or other substances to target cancer cells directly and more precisely destroy cancer. This ideally causes less harm to a patient's normal cells.
Targeted therapy can work in several different ways including
- blocking or decreasing the function of cancer cells' own growth and survival genes and proteins
- blocking or decreasing the development of a tumor's blood supply (angiogenesis inhibitors)
- helping a patient's immune system recognize and kill cancer cells (immunotherapy)
- recognizing specific cancer cells and delivering a drug directly to them (antibody-drug conjugates, ADCs)
Some targeted therapy drugs are biologic medicines, specifically monoclonal antibodies (mAbs), engineered in a laboratory to bind to specific molecules in your cancer or in your body.
Is targeted therapy a treatment option for me?
Current cancer treatment guidelines recommend the use of targeted therapy in advanced colorectal cancer, especially metastatic colorectal cancer (mCRC).
To find out if your cancer might be effectively treated with targeted therapy, you need to have biomarker testing. Biomarker testing is at the center of personalized medicine, an approach in which a person's tumor biomarkers are used to help in the diagnosis and treatment of cancer. Personalized medicine is sometimes called precision medicine.
There are many biomarkers that affect your targeted therapy options.
Microsatellite stability (MSS) describes your tumor cells' ability to do DNA mismatch repair. DNA mismatch repair is the correction of mistakes that occur in DNA when cells grow and divide. There are ongoing clinical trials for targeted therapy and immunotherapy combinations to treat microsatellite stable colorectal cancers. Currently they are treated with conventional chemotherapy and drugs targeting other biomarkers.
Microsatellite instability (MSI-High) describes your tumor cells' deficiency in DNA mismatch repair (also called dMMR). Your tumor cells are unable to correct some mistakes that occur in DNA when cells grow and divide. Colorectal tumors with MSI-High are particularly susceptible to immunotherapy.
KRAS, a member of the RAS family of genes, is involved with control of cell growth and cell survival. Wild-type (normal, non-mutant) KRAS tumors may be treated with EGFR inhibitors. There are ongoing clinical trials testing KRAS inhibitors for colorectal cancer with KRAS mutation, in particular the KRAS G12C mutation, and KRAS mutant tumors may also be treated with traditional chemotherapy in combination with targeted therapies.
NRAS, a member of the RAS family of genes, is involved in control of cell growth and cell survival. Tumors with no NRAS mutation (normal, wild-type) may be treated with EGFR inhibitors. NRAS mutant colorectal cancer may be treated with traditional chemotherapy combined with targeted therapies. Ongoing clinical trials are studying NRAS-specific targeted therapy.
BRAF is a gene involved in control of cell growth. Tumors with BRAF mutations may be treated with BRAF inhibitors.
HER2 is a gene that encodes (gives instructions for making) a protein involved in cell growth and cell survival. HER2 gene amplification or protein overexpression can lead to uncontrolled cell growth and survival of abnormal cells that should die. Colorectal cancer that has HER2 amplification or overexpression can be treated with targeted therapy using HER2 inhibitor drugs. HER2 can also be used as a target for an antibody-drug conjugate (ADC) to deliver a chemotherapy drug to cells that express HER2.
Tumor mutational burden (TMB) is a measurement of how many mutations there are in your tumor‚Äôs genes (tumor DNA), rather than a test of a specific mutation. Patients with TMB-High may be candidates for immunotherapy, even patients who have the MSS biomarker which is not typically treated with immunotherapy.
NTRK fusion is a mutation in which one of the three NTRK genes is fused with a partner gene on another chromosome, creating TRK fusion proteins. It is rare in colorectal cancer, but patients with MSI-High, TMB-High, and wild-type KRAS, NRAS, and BRAF have higher rates of NTRK fusion. NTRK fusion positive patients may be treated with TRK inhibitors.
PIK3CA is a gene involved in the control of cell growth, cell survival, and cell migration. PIK3CA inhibitors, which are treatments that target PIK3CA mutations, are already in use in breast cancer, and are being tested for colorectal cancer in ongoing clinical trials.
For more information about biomarkers and biomarker testing, please visit knowyourbiomarker.org.
What types of targeted therapy drugs are used to treat colorectal cancer?
Angiogenesis Inhibitors: VEGF Inhibitors
A group of targeted drugs that prevent new blood vessels from forming, also called anti-angiogenesis drugs. Tumors need new blood vessels to grow, so stopping new blood vessel formation may prevent cancer growth. VEGF inhibitors block vascular endothelial growth factor (VEGF) binding to VEGF receptors on endothelial cells (the cells that line blood vessels). When VEGF is blocked, new blood vessel formation (angiogenesis) is inhibited, which reduces tumor blood supply and growth. Bevacizumab (Avastin) and ziv-aflibercept (Zaltrap) are VEGF inhibitors.
Angiogenesis Inhibitors: VEGFR Inhibitors
A group of targeted drugs that prevent new blood vessels from forming, also called anti-angiogenesis drugs. Tumors need new blood vessels to grow, so stopping new blood vessel formation may prevent cancer growth. VEGFR inhibitors block VEGF receptors (VEGFRs) on endothelial cells (the cells that line blood vessels). When VEGFRs are blocked, new blood vessel formation (angiogenesis) is inhibited, which reduces tumor blood supply and growth. Ramucirumab (Cyramza) and regorafenib (Stivarga) are VEGFR inhibitors.
These drugs block epidermal growth factor receptor (EGFR). EGFR is involved in cell growth. Blocking EGFR can reduce the uncontrolled cell growth and cell proliferation of cancer cells. Cetuximab (Erbitux) and panitimumab (Vectibix) are EGFR inhibitors used in colorectal cancer treatment.
This group of targeted therapy drugs blocks the HER2 receptor. In cancer cells that have increased HER2 expression, HER2 inhibition can lead to decreased cancer cell proliferation. Trastuzumab (Herceptin), pertuzumab (Perjeta), and tucatinib (Tukysa) are HER2 inhibitors used in the treatment of colorectal cancer. Lapatinib (Tykerb) is a dual HER2 and EGFR inhibitor used to treat CRC. Fam-trastuzumab deruxtecan-nxki (Enhertu) is a combination of a HER2 inhibitor and a conventional chemotherapy drug used in CRC treatment.
These targeted therapy drugs block the BRAF protein, which is involved in cell growth control. Blocking BRAF can reduce cancer cell growth. Encorafenib (Braftovi) and vemurafenib (Zelboraf) are BRAF inhibitors used in the treatment of colorectal cancer that has a V600E BRAF gene mutation. BRAF inhibitors are usually given in combination with MEK inhibitors.
The MEK1 and MEK2 proteins are involved in control of cell growth and cell survival. MEK inhibitors, given in combination with BRAF inhibitors, block these proteins, reducing cancer cell growth and survival. The MEK inhibitors used in CRC are binimetinib (Mektovi), cobimetinib (Cotellic), and trametinib (Mekinist).
NTRK gene fusion is a driver of several different types of cancer, including colon cancer and rectal cancer. TRK inhibitors are used to treat colorectal cancer with NTRK gene fusion. TRK inhibitors block TRK fusion proteins, reducing cancer cell growth. Larotrectinib (Vitrakvi) and entrectinib (Roxlytrek) are TRK inhibitors.
KRAS is a protein that acts as an on/off switch for cell growth. When the KRAS gene has a mutation, the protein may get stuck in the on position. KRAS inhibitors work by locking the abnormal protein into the off position. While still in clinical trials for colorectal cancer, adagrasib (Krazati) and sotorasib (Lumakras) have already been approved for treatment of lung cancer with a KRAS G12C mutation. In combination with cetuximab, adagrasib has received a breakthrough therapy designation from the United States Food and Drug Administration (FDA). For more information about participating in a clinical trial, check out our Clinical Trial Awareness program.
These targeted therapy drugs work by blocking abnormal (mutant) PIK3CA protein. PIK3CA is involved in the control of cell growth and cell migration. While it is still in clinical trials for colorectal cancer, alpelisib (Piqray) has already been approved for treatment of breast cancer that has a PIK3CA gene mutation. For more information about participating in a clinical trial, please check out our Clinical Trial Awareness program.
What is tumor-agnostic targeted therapy?
As the understanding of cancer has grown, it has become clear that the location and cell type of a cancer are not the only aspects that inform treatment. Biomarker testing has shown that tumors originating in different parts of the body may have more in common than once thought; they can have the same tumor markers, or a similar set of tumor markers called a molecular signature. Because of this, targeted therapy drugs are being developed, studied, and approved in a way that does not depend on tumor location, but on their molecular type. This has led to drugs with indications like‚ "unresectable or metastatic solid tumors with a specific biomarker". This has expanded the treatment options for colorectal cancer patients whose tumor markers are not common in CRC but may be common in other cancers. For example, HER2 abnormalities are common in breast cancer, and targeted treatments for HER2 positive breast cancer have been established. Because of tumor-agnostic trials, some of these HER2 inhibitors are now known to help in other HER2 positive cancers such as gastric cancer, gastroesophageal cancer, and colorectal cancer. Similarly, because of tumor-agnostic trials, it has been discovered that KRAS inhibitors initially approved for lung cancer may also be a treatment option for colorectal cancer.
How are targeted therapy drugs given?
Different targeted therapy drugs may be administered as a pill by mouth (orally) or as a liquid by infusion in a vein (intravenously).
Targeted therapy is often prescribed in combination with conventional chemotherapy drugs for colorectal cancer. Targeted therapy may also be used alongside immunotherapy drugs including immune checkpoint inhibitors like ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda).
What are the side effects of targeted therapy?
The side effects of targeted therapy depend on which drug is being used. Common side effects of VEGF inhibitors and VEGFR inhibitors include mouth sores, loss of appetite, diarrhea, headache, fatigue, high blood pressure, bleeding, and increased risk of infection due to low white blood cell count. EGFR inhibitors commonly cause skin rashes, and the presence and severity of this skin side effect may indicate a better treatment outcome with the drug. Headache, fatigue, fever, and diarrhea may also be side effects of EGFR inhibitors. Common side effects of HER2 inhibitors include skin rash, nausea, vomiting, diarrhea, and fatigue. Specific HER2 inhibitors are associated with less common severe side effects including heart problems, liver problems, and lung disease. The combination of BRAF inhibitors and MEK inhibitors may cause skin problems, loss of appetite, fatigue, nausea, diarrhea, abdominal pain, and joint pain. Common side effects of TRK inhibitors include nausea, vomiting, diarrhea, constipation, fatigue, dizziness, and weight gain.
Talk to your oncology team about potentially serious side effects of specific targeted therapy drugs before you start taking them and be sure to tell your healthcare team about any side effects you experience.