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.