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.
AuthorsJanghee Woo, Neil Palmisiano, William Tester, John C Leighton Jr
JournalCancer (Cancer) Vol. 119 Issue 11 Pg. 1941-50 (Jun 1 2013) ISSN: 1097-0142 [Electronic] United States
PMID23504768 (Publication Type: Journal Article, Review)
CopyrightCopyright © 2013 American Cancer Society.
Chemical References
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Receptor, Epidermal Growth Factor
  • Cetuximab
  • Antibodies, Monoclonal, Humanized (administration & dosage, therapeutic use)
  • Antineoplastic Agents (administration & dosage, therapeutic use)
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Cetuximab
  • Clinical Trials, Phase III as Topic
  • Colorectal Neoplasms (drug therapy, genetics, pathology)
  • Humans
  • Neoplasm Metastasis
  • Protein Kinase Inhibitors (administration & dosage, therapeutic use)
  • Randomized Controlled Trials as Topic
  • Receptor, Epidermal Growth Factor (antagonists & inhibitors, metabolism)

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