Monoclonal antibodies in the treatment of metastatic colorectal cancer: A review

doi:10.1016/j.clinthera.2010.03.012

Clinical Therapeutics

Volume 32, Issue 3, March 2010, Pages 437-453

https://doi.org/10.1016/j.clinthera.2010.03.012 Get rights and content

Abstract

Background: Two groups of agents targeting either the vascular endothelial growth factor (VEGF) receptor or the epidermal growth factor receptor (EGFR) have been added to the therapeutic arsenal against metastatic colorectal cancer (mCRC). Currently available agents in these groups are the anti-VEGF antibody bevacizumab and the anti-EGFR antibodies cetuximab and panitumumab.

Objectives: This article reviews the results of prospective randomized clinical trials of anti-VEGF and anti-EGFR antibodies in mCRC, either as monotherapy, combined with chemotherapy, or combined with each other. Also reviewed are retrospective subset analyses of the effect of a KRAS mutation on the response to anti-EGFR antibodies.

Methods: MEDLINE (2004–2009) was searched for randomized Phase II-III clinical trials of monoclonal antibodies in mCRC published in English. The search terms were colorectal neoplasms, bevacizumab, cetuximab, panitumumab, and KRAS mutation, alone or in combination. Information on the effect of KRAS mutation status on the response to anti-EGFR antibodies was drawn from retrospective subset analyses within the selected trials.

Results: The literature search identified 5 trials of bevacizumab in mCRC. Of these trials, 3 found a significant benefit on the primary end point (progressionfree survival [PFS] or overall survival [OS]) when bevacizumab was added to chemotherapy, either as first-line (2 trials) or second-line (1 trial) treatment. The literature search identified 5 trials of cetuximab and 1 trial of panitumumab in mCRC. Of these trials, 4 found a significant benefit on the primary end point (response rate, PFS, or OS) with cetuximab or panitumumab as monotherapy or added to chemotherapy, either as first-line (1 trial) or later-line (3 trials) treatment. In all trials, the benefit of anti-EGFR therapy was limited to patients who had KRAS wild-type tumors. Of 3 identified trials of combined anti-EGFR and anti-VEGF therapy, 2 found that the combination of an anti-EGFR antibody and the anti-VEGF antibody bevacizumab had a significant negative effect on the primary end point (PFS) compared with no added anti-EGFR antibody.

Conclusions: In the studies reviewed, the anti-VEGF antibody bevacizumab added to chemotherapy and the anti-EGFR antibodies cetuximab and panitumumab as monotherapy or added to chemotherapy were associated with consistent efficacy in the treatment of mCRC, although the absolute benefit differed among trials. The efficacy of anti-EGFR antibodies was limited to patients with KRAS wild-type tumors. Given the lack of benefit when anti-VEGF and anti-EGFR antibodies were combined, such regimens should not be used in clinical practice.

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Monoclonal antibodies in the treatment of metastatic colorectal cancer: A review

Abstract

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Ann Oncol.

Eur J Cancer.

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Oncologist.

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J Clin Oncol.

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J Clin Oncol.

Capecitabine and irinotecan as first-line treatment of advanced colorectal cancer

J Clin Oncol.

Targeting signal transduction pathways in colorectal cancer—more than skin deep

J Clin Oncol.

Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everoli-mus: A phase I tumor pharmacody-namic study in patients with advanced solid tumors

J Clin Oncol.

Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor

Clin Cancer Res.

Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer

J Clin Oncol.

Clinical relevance of KRAS mutation detection in meta-static colorectal cancer treated by Cetuximab plus chemotherapy

Br J Cancer.

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J Clin Oncol.

The biology of VEGF and its receptors

Nat Med.

Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis

Oncogene.

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J Clin Oncol.

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Br J Cancer.

The influence of invasive growth pattern and microvessel density on prognosis in colorectal cancer and colorectal liver metastases

BrJ Cancer.

Impact of vascular endothelial growth factor-A expression, throm-bospondin-2 expression, and mi-crovessel density on the treatment effect of bevacizumab in metastatic colorectal cancer

J Clin Oncol.

The epidermal growth factor receptor pathway: A model for targeted therapy

Clin Cancer Res.

Epidermal growth factor receptor immunohis-tochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarci-noma: Implications for a standardized scoring system

Cancer.

A simple and reproducible scoring system for EGFR in colorectal cancer: Application to prognosis and prediction of response to preopera-tive brachytherapy

Br J Cancer.

Clinicopathologic significance of EGFR and Her-2/neu in colorectal adenocarcinomas

Cancer J.

Relationships of insulin-like growth factor-1 receptor and epidermal growth factor receptor expression to clinical outcomes in patients with colorectal cancer

Oncology.