Four actionable targets for metastatic colorectal cancer

In the past two years, findings from important clinical trials are shaping a new approach to treating different subgroups of patients with metastatic colorectal cancer (mCRC). Today, screening patients for biomarkers such as microsatellite instability status, BRAFV600E, HER2 and neurotrophic tyrosine receptor kinase (NTRK) is understood to be a fundamental step in developing a treatment approach that is best tailored to the patient.

But first, what is a cancer biomarker?

According to the World Health Organization, a cancer biomarker is “any substance, structure or process that can be measured in the body and influences or predicts the incidence of disease”. Biomarkers can help to measure the risk of developing cancer in a specific tissue, or can help to better understand the risk of cancer progression or potential response to therapy. Biomarker testing is being increasingly acknowledged as a crucial step towards more personalized, effective medicine.

Microsatellite instability

Microsatellite instability-high (MSI-H) and mismatch repair deficient (dMMR) status are important colorectal cancer biomarkers that occur in about 5% of mCRC. MSI-H/dMMR occurs when a cell is unable to repair mistakes made during the cell division process, leading to accumulations of errors in sequences of DNA called microsatellites.

The KEYNOTE-177 study compared the immunotherapy drug pembrolizumab (Keytruda, Merck) with standard chemotherapy as initial treatment for patients with MSI-high mCRC, which typically has poor disease outcomes. Findings showed that pembrolizumab significantly improved progression-free survival (the time following treatment that the patient lives without their cancer getting worse) with a higher overall response rate and fewer side effects compared to chemotherapy.

BRAFV600E

BRAFV600E is another biomarker which, when present, leads to poor disease outcomes. BRAFV600E is a mutation that occurs in the BRAF gene, which, alongside other proteins such as EGFR or MEK, is involved in cell growth and division. Findings from the phase III BEACON CRC clinical trial found that dual and triple inhibition of BRAF-EGFR, or BRAF-EGFR-MEK with targeted therapy drugs resulted in better disease outcomes compared to standard chemotherapy among this subset of mCRC patients.

The ongoing ANCHOR study is investigating the effects of BRAF-EGFR inhibition as first-line therapy among patients with BRAFV600E-positive mCRC.

HER2 amplification

A small subset of patients with mCRC demonstrates HER2 amplification or overexpression, a gene that is also involved in metastatic breast cancer. The MyPathway trial examined the effectiveness of pertuzumab (Perjeta, Genentech) in combination with trastuzumab (Herceptin, Genentech) for HER2-positive mCRC. Results showed a promising response rate among patients who had been treated unsuccessfully with other therapies.

NTRK fusion

Patients with mCRC who test positive for the rare NTRK fusions now have several promising treatment options based on evidence from recent clinical trials. Larotrectinib (Vitrakvi, Bayer) and entrectinib (Rozlytrek, Genentech) are TRK inhibitors that have been approved for the treatment of mCRC patients with NTRK fusions, showing longer-lasting response rates compared to standard of care.

These exciting new therapies reinforce the importance of biomarker testing on patients to best tailor their treatment to their disease. For more information on biomarker testing, visit Colorectal Cancer Alliance’s Biomarkers 101 page.