Biomarkers, targeted and immunotherapies for colorectal cancer
This section covers the following topics:
Biomarker tests look at samples of blood, tumor or other tissue for changes or abnormalities caused by cancer. These tests can give doctors clues about the cancer, including:
- how fast the cancer is growing
- which treatments are most likely to work
- whether or not the cancer is responding to treatment or growing
- whether or not the cancer has come back after remission
Biomarkers for treatment selection
Biomarker tests may be used to select treatments, and help patients avoid side effects from treatments that will not work for them. Biomarker tests used to select a specific treatment are sometimes called "companion diagnostic tests." These tests may be done on tumor tissue or (in many cases) on blood. See our Biomarker Testing section for more information.
- Experts recommend testing all colorectal cancers for an abnormality known as MSI-H (“microsatellite instability high") also known as "mismatch repair deficiency" (dMMR or MMR-D).
- Experts recommend testing metastatic colorectal cancers for the following biomarkers:
- A specific mutation in a gene known as BRAF. Tumors with the mutation called V600E, may respond to targeted therapies known as BRAF inhibitors.
- HER2 (also known as HER2/neu or ERBB2) is a biomarker commonly used in breast cancer to select patients who would benefit from anti-HER2 therapy (for example Herceptin (trastuzumab). In advanced colorectal cancer, tumors that test negative for RAS and BRAF mutations may be tested for HER2. Tumors that test positive for HER2 may be treated with Herceptin, usually in combination with standard chemotherapy.
- Additional biomarker tests that may be used in colorectal cancer:
- A biomarker known as an NTRK fusion is rare in colorectal cancer. Advanced/metastatic colorectal cancer with an NTRK fusion may benefit from the targeted therapy Vitrakvi (larotrectinib).
- Additional tumor biomarker testing may help people learn if they are eligible for certain clinical trials.
Immunotherapies help the body’s immune system detect and attack cancer cells.
- Immune checkpoint inhibitors are often used to treat advanced or metastatic colorectal cancer that have MSI-H or dMMR; usually after other treatments have been tried. The most common immune checkpoint inhibitors used for colorectal cancer are:
- Keytruda (pembrolizumab)
- Opdivo (nivolumab)
- Yervoy (ipilimumab)
Several targeted therapies are used to treat advanced or metastatic colorectal cancer. Some work best for people with or without a certain biomarker.
- Anti VEGF therapies block tumors from forming blood vessels. Anti VEGF drugs used to treat colorectal cancer include:
- Avastin (bevacizumab)
- Cyramza (ramucirumab)
- Zaltrap (ziv-aflibercept)
- Anti EGFR therapies slow down tumor cell growth. Anti EGFR drugs used to treat colorectal cancer include:
- Erbitux (cetuximab)
- Vectibix (panitumumab)
- BRAF inhibitors are oral medications that help slow down tumor growth in advanced colorectal cancers that test positive for the tumor biomarker called a BRAF V600E mutation. BRAF inhibitors are usually given in combination with other oral targeted drugs called MEK inhibitors (e.g., trametinib [Mekinist] or binimetinib [Mektovi]). BRAF inhibitors include:
- Tafinlar (dabrafenib)
- Braftovi (encorafenib)
- Stivarga (regorafenib) blocks several different types of proteins in the body that tumors use to grow. Stivarga may be used to treat metastatic colorectal cancer that has come back after treatment with other drugs.
- Herceptin (trastuzumab) is used to treat advanced or recurrent HER2-positive colorectal cancers that do not have a BRAF, KRAS or NRAS mutation.
- Vitrakvi (larotrectinib) is approved for treatment of advanced cancers that have worsened with other treatments. It targets a genetic change called an NTRK fusion. This type of genetic change is found in a range of cancers, including some colon cancers.
Table of targeted and immunotherapies for colorectal cancer
|Name of drug||Type of agent||Cancer stage||Indication||Biomarker|
|Keytruda (pembrolizumab)||Immune checkpoint inhibitor||Metastatic or unresectable colorectal cancer||For first-line treatment of metastatic or unresectable colorectal cancer||Microsatellite Instability High (MSI-H) or Mismatch Repair Deficiency (MMR-D)|
|Metastatic or unresectable solid tumors||For treatment of solid tumors that have progressed after treatment and for which there are no other treatment options||Microsatellite Instability High (MSI-H) or Mismatch Repair Deficiency (MMR-D)|
|Metastatic or unresectable solid tumors||For the treatment of solid tumors that have progressed after treatment and for which there are no other treatment options||Tumor Mutational Burden High (TMB-H)|
|Metastatic or unresectable colorectal cancer||Cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan||Microsatellite Instability High (MSI-H) or Mismatch Repair Deficiency (MMR-D)|
|Immune checkpoint inhibitor||Metastatic colorectal cancer||
As a single agent or in combination with Yervoy (ipilimumab) for cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
|Microsatellite Instability High (MSI-H) or Mismatch Repair Deficiency (MMR-D)|
|Yervoy (ipilumumab)||Immune checkpoint inhibitor||Metastatic colorectal cancer||Combined with Opdivo (nivolumab) for cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan||Microsatellite Instability High (MSI-H) or Mismatch Repair Deficiency (MMR-D)|
|Monoclonal antibody for vascular endothelial growth factor (VEGF)||Metastatic colorectal cancer||Combined with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment||No biomarker required|
|Metastatic colorectal cancer||In combination with chemotherapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen||No biomarker required|
|Monoclonal antibody for vascular endothelial growth factor (VEGF)||Metastatic colorectal cancer||Combined with FOLFIRI chemotherapy, for treatment after disease progression on, or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine||No biomarker required|
|Monoclonal antibody for epidermal growth factor receptor (EGFR)||Metastatic colorectal cancer||Combined with FOLFIRI for first-line treatment, or combined with irinotecan for cancers that no longer respond to irinotecan-based chemotherapy or as a single agent in patients who have progressed after oxaliplatin- and irinotecan-based chemotherapy||EGFR positive and KRAS mutation negative|
|Monoclonal antibody for epidermal growth factor receptor (EGFR)||Metastatic colorectal cancer||Combined with FOLFOX for first-line treatment||Negative for KRAS and NRAS tumor mutations|
|Metastatic colorectal cancer||As a single therapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy||Negative for KRAS and NRAS tumor mutations|
The following studies may be of interest to people with colorectal cancer and an inherited mutation.
Advanced solid tumors of any type
- NCT04082572: Pembrolizumab Before Surgery for the Treatment of Mismatch Repair Deficient Locally Advanced Solid Cancers. This trial studies how well the immunotherapy agent, pembrolizumab works before surgery in treating patients with mismatch repair deficient solid cancers that have spread to nearby tissue or lymph nodes (locally advanced). This study may be of particular interest to people with a mutation in a Lynch syndrome gene.
- NCT04001101: A Randomized Phase II Study of Anti-PD-1 and Limited Metastatic Site Radiation Therapy Versus Anti-PD-1 Alone for Patients With Microsatellite Instability-high (MSI-H) and Mismatch Repair Deficient (dMMR) Metastatic Solid Tumors. To determine if treatment is improved with the addition of radiation therapy to anti-PD-1 for patients with MSI-H/dMMR metastatic solid tumors. This study may be of particular interest to people with a mutation in a Lynch syndrome gene.
- NCT03607890: Study of Nivolumab and Relatlimab in Advanced Mismatch Repair Deficient Cancers Resistant to Prior PD-(L)1 Inhibitor. The purpose of this study is to evaluate the safety and clinical activity of nivolumab and relatlimab in patients with microsatellite instability high (MSI-H) solid tumors refractory to prior PD-(L)1 therapy. This study may be of particular interest to people with a mutation in a Lynch syndrome gene.
- NCT04041310: Nous-209 Genetic Vaccine for the Treatment of Microsatellite Unstable Solid Tumors. NOUS-209-01 is a multicenter, open-label, multiple cohorts, First In Humans (FIH) clinical study, designed to evaluate safety, tolerability, and immunogenicity, and to detect any preliminary evidence of anti-tumor activity of Nous-209 genetic polyvalent vaccine. This study may be of particular interest to people with a mutation in a Lynch syndrome gene.
- NCT03832569: Study of Pembrolizumab or Placebo Following Surgery in Patients With Microsatellite Instability High (MSI-H) Solid Tumors. This study tests the safety of the drug, pembrolizumab, and to find out how well it works to prevent cancer from coming back in people who have had a solid tumor surgically removed, but still have tumor cells in their blood. This study may be of particular interest to people with a mutation in a Lynch syndrome gene.
- NCT02715284: A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET). This study may be of particular interest to people with a mutation in a Lynch syndrome gene.
- NCT03767348: Study of RP1 Monotherapy and RP1 in Combination With Nivolumab. RPL-001-16 is a clinical study of RP1 alone and in combination with nivolumab in adult subjects with advanced and/or refractory solid tumors, to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), as well as to evaluate preliminary efficacy.This study may be of particular interest to people with a mutation in a Lynch syndrome gene.
- NCT03589339: NBTXR3 Activated by Radiotherapy for Patients With Advanced Cancers Treated With An Anti-PD-1 Therapy. The 1100 study is an open-label, Phase I, prospective clinical study to assess the safety of intratumoral injection of NBTXR3 activated by radiotherapy in combination with anti-PD-1 therapy. This study may be of particular interest to people with a mutation in a Lynch syndrome gene.
- NCT03517488: A Study of XmAb®20717 in Subjects With Selected Advanced Solid Tumors (DUET-2). This is a Phase 1, multiple dose, ascending dose escalation study to define a MTD/RD and regimen of XmAb20717, to describe safety and tolerability, to assess PK and immunogenicity, and to preliminarily assess anti-tumor activity of XmAb20717 in subjects with selected advanced solid tumors, including colorectal cancers with MSI-H.
- https://clinicaltrials.gov/ct2/show/NCT03436563: M7824 in Patients With Metastatic Colorectal Cancer or With Advanced Solid Tumors With Microsatellite Instability. Thistrial studies how well anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) works in treating patients with colorectal cancer (or with other solid tumors with microsatellite instability) that has spread to other places in the body or cannot be removed by surgery.
- NCT03228667: QUILT-3.055: A Study of ALT-803 in Combination With PD-1/PD-L1 Checkpoint Inhibitor in Patients With Advanced Cancer. This is a Phase IIb, single-arm, multicohort, open-label multicenter study of ALT-803 in combination with an FDA-approved PD-1/PD-L1 checkpoint inhibitor in patients with advanced cancers who have progressed following an initial response to treatment with PD-1/PD-L1 checkpoint inhibitor therapy.
- NCT03375320: Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated With Everolimus That Are Locally Advanced, Metastatic, or Cannot Be Removed by Surgery. This study is looking at cabozantinib S-malate to see how well it works compared with placebo in treating patients with neuroendocrine tumors previously treated with everolimus that have spread to nearby tissues or lymph nodes, have spread to other places in the body, or cannot be removed by surgery.