Ongoing research is focused on optimizing targeted therapy use in metastatic colorectal cancer (mCRC) by integrating these treatments into earlier lines of therapy. Molecular testing at diagnosis is now standard of care, enabling the identification of actionable mutations that can be targeted with specific therapies.
Molecular Testing and Targeted Therapy Options
Aparna Parikh, MD, from Massachusetts General Hospital, emphasized the importance of molecular testing in mCRC to determine eligibility for various targeted therapies. Patients with microsatellite instability-high (MSI-H) tumors may benefit from immune checkpoint inhibitors in the first line. For other patients, targeted therapies directed against BRAF, HER2, and RAS mutations are available in later lines of treatment, with clinical trials exploring their use in earlier lines.
BRAF-Targeted Therapy
Approximately 5% to 10% of mCRC patients have the BRAF V600E mutation. The BEACON regimen, consisting of the BRAF inhibitor encorafenib and the anti-EGFR antibody cetuximab, has shown efficacy in the second-line setting after progression on first-line chemotherapy. This regimen was evaluated in the phase 3 BEACON CRC trial (NCT02928224). The BREAKWATER study (NCT04607421) is evaluating the regimen in the first line in combination with chemotherapy.
HER2-Targeted Therapies
HER2 amplification, rather than mutation, is more commonly observed in CRC. The phase 2 MOUNTAINEER trial (NCT03043313) led to the FDA approval of trastuzumab plus tucatinib for HER2-positive mCRC in the second line. Additionally, the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) has demonstrated effectiveness in patients with HER2-high disease, particularly those with amplified HER2 by fluorescence in situ hybridization or immunohistochemistry. T-DXd may be considered after trastuzumab plus tucatinib or in patients with KRAS mutations.
Novel Approaches and Ongoing Trials
The phase 3 MOUNTAINEER-03 trial (NCT05253651) is investigating the addition of chemotherapy to the MOUNTAINEER regimen in the first-line setting for HER2-positive mCRC. Furthermore, a pipeline of new RAS-targeted therapies, including pan-KRAS inhibitors, is under development. Therapies targeting KRAS G12C and G12D mutations are also being explored in clinical trials.
