Biologics and immunotherapy in metastatic colorectal cancer

Abstract

The outcome of patients with metastatic colorectal cancer (CRC) has dramatically improved in the last two decades with the availability of more cytotoxic drugs and biologic agents with activity in this disease. In 2015, combination regimens of chemotherapy paired with a biologic such as a VEGF-inhibitor or EGFR antibody are considered standard of care in the management of patients with advanced CRC. The search for pre-treatment biomarker to help guide treatment decisions has only born fruit with regard to the EGFR antibodies since RAS/RAF mutations have been recognized as negative predictive markers of activity of this class of agents. Immunotherapeutic agents, in particular, immune checkpoint modulators, have made inroads into various tumor entities like melanoma, non-small lung cancer, bladder, and gastric cancer. Early results anti-CTLA-4, and anti-PD-1/PD-L1 agents were not encouraging in unselected patients with CRC. The realization, however, that CRC exhibiting an hypermutated phenotyp, i.e. CRC characterized by microsatellite instability can elicit an immune response by the host, has opened the door for various clinical trials in this specific subgroup of patients. In addition, combination regimens of PD-1/PD-l1 inhibitors with chemotherapy and VEGF inhibitors like bevacizumab have shown intriguing early signs of activity so that immunotherapeutic approaches might still have a future in the management of metastatic CRC.