Treatment Refractory Metastatic Colorectal Cancer

Patients with metastatic colorectal cancer are treated with biochemotherapy in the first-line setting with promising response rates. However, most patients will eventually progress and need subsequent lines of therapy. Multiple therapies including targeted therapies are available and administration of these therapies depends on a patient’s performance status, prior treatment, and molecular profile. Notable molecular subsets include patients with deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H) tumours, where immune checkpoint therapy has demonstrated durable responses; BRAFV600 mutant tumours, where combined BRAF and EGFR inhibition has shown improved response rate and survival; and HER2 amplified or overexpressed tumours, where dual anti-HER2 therapy and HER2 antibody drug conjugates have shown robust efficacy. Barring these subsets, a large proportion of patients with metastatic colorectal cancer are treated with second/third-line chemotherapy. In the salvage setting, two oral drugs, regorafenib and TAS-102, have shown survival benefit over placebo. Despite these options, survival is limited. Consequently, novel therapeutics is an area of great unmet need and active investigation.