Optimal sequencing strategies in metastatic colorectal cancer

Dr. Heinz-Josef Lenz, MD, discusses optimal sequencing strategies for the treatment of patients with metastatic colorectal cancer (mCRC):

Numerous therapeutic agents are currently available for the treatment of mCRC. This makes the sequencing, or the order in which these agents are administered, an important factor in optimizing a patient’s treatment. First-line or initial therapy remains straight forward, consisting of a chemotherapy backbone given in combination with targeted agents, which will vary depending on the molecular testing of the patient’s tumour. In the case that the patient does not have RAS or BRAF mutations, then targeted agents such as EGFR inhibitors are a worthwhile option. If the patient does have RAS or BRAF mutations in their tumour, anti-VEGF targeted agents such as bevacizumab (Avastin) can be used.

If chemotherapy in the first- and second-line settings proves to be ineffective, third-line options can include agents such as regorafenib (Stivarga, not currently reimbursed in Canada) and trifluridine, tipiracil (TAS-102; Lonsurf, currently reimbursed only in Quebec). New findings from clinical trials have also suggested that the reuse of chemotherapy and targeted agents such as EGFR inhibitors in later lines of treatment may be effective. For example, when an EGFR inhibitor is used in the first-line setting and shows some positive effect measured by response rate or progression-free survival but the patient begins to develop resistance to the drug, switching to an alternative regimen like bevacizumab-based chemotherapy for some time may result in the “lifting” of the mechanism of resistance. Reuse of EGFR inhibitors in later lines showed a response rate between 20-30%, increasing when biomarker testing was used to determine whether an underlying mechanism of resistance is present, such as RAS or BRAF mutations, which are the most common mechanisms of EGFR resistance.