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Review
. 2023 Dec 11;28(12):1034-1048.
doi: 10.1093/oncolo/oyad262.

Anti-EGFR Antibodies in the Management of Advanced Colorectal Cancer

Pashtoon Murtaza Kasi  1 , Manuel Geroy Afable  2 , Cameron Herting  2 , Mariusz Lukanowski  2 , Zhaohui Jin  3
Affiliations
Review

Anti-EGFR Antibodies in the Management of Advanced Colorectal Cancer

Pashtoon Murtaza Kasi et al. Oncologist. .

Abstract

Colorectal cancer is the third most common cancer worldwide, and incidence is rising in younger individuals. Anti-EGFR antibodies, including cetuximab and panitumumab, have been incorporated into standard-of-care practice for patients with advanced disease. Herein, we review the molecular characteristics of these agents and the trials that lead to their approvals. Further, we discuss clinical implications of data regarding biomarkers that dictate treatment selection, different dosing strategies, and side effect management. Finally, we look towards the future and describe contexts in which these agents are currently being investigated clinically with a focus on combinations with MAPK-targeted therapies and immunotherapy. Overall, this review provides historical context, current clinical usage, and future directions for anti-EGFR antibodies in advanced colorectal cancer.

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Conflict of interest statement

Pashtoon Murtaza Kasi owns stock in Elicio Therapeutics; has consulted or advised for Natera, Foundation Medicine, MSD Oncology, Tempus, Bayer, Eli Lilly, Delcath Systems, QED Therapeutics, Servier, Taiho Oncology, Exact Sciences, Daiichi Sankyo/AstraZeneca, Eisai, Seattle Genetics, SAGA Diagnostics, Illumina, BostonGene, NeoGenomics Laboratories, Elicio Therapeutics, and Ipsen; has received institutional research funding from Advanced Accelerator Applications, Tersera, and Boston Scientific; and has received reimbursement for travel expenses from AstraZeneca. Manuel Geroy Afable and Cameron Herting are employees of Eli Lilly and Company. Mariusz Lukanowski was an employee of Eli Lilly and Company, with ownership interests, until the finalization of this review article and left the organization at the time of submission. Zhaohui Jin has received institutional funding for scientific advising from QED Therapeutics, Novartis, Daiichi Sankyo/AstraZeneca, Eli Lilly, and GSK.

Figures

Figure 1.
Figure 1.
Biomarker testing flowchart. This flowchart displays biomarkers that govern selection of FDA-approved regimens in mCRC and highlights how these are typically assessed in patient samples.
Figure 2.
Figure 2.
Current clinical development focus for cetuximab and panitumumab in mCRC. (A) The phases of open clinical trials with cetuximab and panitumumab in mCRC. (B) Patient populations assessed in open clinical trials with cetuximab and panitumumab in mCRC. (C) Illustration of drug classes paired with cetuximab and panitumumab in open trials in mCRC. Depiction of number of trials where cetuximab and panitumumab are paired with (D) MAPK-targeted approaches or (E) immunotherapy. Abbreviations: WT: wild type; mut: mutant; pos.: positive.
Figure 3.
Figure 3.
The MAPK pathway and MAPK-targeted approaches under development in CRC. The MAPK pathway is illustrated with agents that target components of the pathway depicted. The dotted arrow indicates reactivation of the MAPK pathway seen following administration of a MAPK-targeted therapy. Abbreviations: BRAF: B-RAF proto-oncogene, serine/threonine kinase; CDK4/6: cyclin-dependent kinase 4/6; EGFR: epidermal growth factor receptor; ERK1/2: extracellular signal-regulated kinase 1/2; GTP: guanosine triphosphate; MEK1/2: mitogen-activated protein kinase 1/2; mTOR: mammalian target of rapamycin; P: phosphate group; PI3K: phosphoinositide 3-kinases; PTEN: phosphatase and tensin homolog; Rb: retinoblastoma; RAF: rapidly accelerated fibrosarcoma; RAS: rat sarcoma virus; RTK: receptor tyrosine kinase; SHP2: SH2 domain-containing tyrosine phosphatase 2; SOS: son of sevenless.
Figure 4.
Figure 4.
Antibody-dependent cellular cytotoxicity (ADCC). ADCC activation by cetuximab is demonstrated. The Fc region of cetuximab binds to natural killer cell receptor CD16/FcγRIII for the activation of the process 2a. Natural killer cells release tumor antigens 2b. Crosstalk between NK cells and dendritic cells through the release of interferon-gamma, chemokines, and cytokines 3a. These changes lead to tumor cell apoptosis 3b. Presentation of tumor antigens by dendritic cells to T cells leading to tumor cell lysis. Abbreviations: EGFR: epidermal growth factor receptor; Fc: fragment crystallizable.
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