Controversies in antiepidermal growth factor receptor therapy in metastatic colorectal cancer

Authors

  • Janghee Woo MD, PhD,

    Corresponding author
    1. Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania
    • Corresponding author: John C. Leighton, Jr., MD, Braemer Cancer Center, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141; Fax: (215) 456-3824; leightoj@einstein.edu and Janghee Woo, MD, PhD, Department of Medicine, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141; Fax: (215)-456-7926; woojangh@einstein.edu

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  • Neil Palmisiano MD,

    1. Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
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  • William Tester MD,

    1. Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania
    2. Braemer Cancer Center, Albert Einstein Medical Center, Philadelphia, Pennsylvania
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  • John C. Leighton Jr. MD

    Corresponding author
    1. Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania
    2. Braemer Cancer Center, Albert Einstein Medical Center, Philadelphia, Pennsylvania
    • Corresponding author: John C. Leighton, Jr., MD, Braemer Cancer Center, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141; Fax: (215) 456-3824; leightoj@einstein.edu and Janghee Woo, MD, PhD, Department of Medicine, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141; Fax: (215)-456-7926; woojangh@einstein.edu

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Abstract

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.

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