Controversies in antiepidermal growth factor receptor therapy in metastatic colorectal cancer

The randomized first‐line trials, including the CRYSTAL trial, the OPUS trial, and the PRIME trial, have demonstrated the significant efficacy of cetuximab or panitumumab in patients with v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild‐type tumors. The addition of an antiepidermal growth factor receptor (anti‐EGFR)‐directed monoclonal antibody to chemotherapy for these patients significantly improved progression‐free survival, response rates, and R0 resection rates to a greater extent than overall survival compared with patients who received chemotherapy alone. However, 2 recent randomized phase 3 trials, the MRC COIN trial and the Nordic VII trial, reported an unexpected lack of benefit from the addition of cetuximab to chemotherapy in the first‐line setting. In addition, recent retrospective analyses performed on a pooled data set from major clinical trials added more complexity, reporting an unexpected association of KRAS G13D mutation with a better clinical outcome compared with patients who had other KRAS mutations in the first‐line and salvage settings, whereas the other independent analysis failed to demonstrate a benefit from panitumumab in patients with the same KRAS G13D mutation. The anti‐EGFR monoclonal antibody‐associated skin toxicity and the controversial strategies of management also are discussed. In this review, the authors analyze the previous randomized clinical trials and more critically re‐evaluate recent trials and subgroup analyses to derive 3 factors that need to be taken into consideration regarding the addition of EGFR‐directed monoclonal antibodies to chemotherapy: the preclinical data on mechanisms of action between chemotherapy and anti‐EGFR antibodies along with mechanisms of resistance to anti‐EGFR antibodies, the role of cross‐over events in overall survival data, and the significant dose reductions of chemotherapeutic agents when combined with anti‐EGFR agents. Cancer 2013;119:1941–1950. © 2013 American Cancer Society.