Introduction

Cetuximab (brand name Erbitux) is a monoclonal antibody used in the treatment of metastatic colorectal cancer (mCRC) and cancer of the head and neck. Cetuximab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered as a weekly intravenous (IV) infusion, but in practice, is often given every other week to coincide with chemotherapy (for example, FOLFIRI or FOLFOX). Cetuximab has several off-label uses as well, which include non-small cell lung cancer, squamous cell carcinoma of the skin, and Menetrier’s disease.

Interestingly, for colorectal cancer, the location of the primary tumor influences whether an individual with mCRC will respond to anti-EGFR therapy, and influences prognosis. Individuals with left-sided tumors are more likely to respond well to anti-EGFR therapy and have a better prognosis. Individuals with right-sided tumors have a worse prognosis and respond poorly to anti-EGFR therapy. However, currently only the mutation status of the tumor, and not the location of the tumor, is discussed in the drug label’s dosing recommendations.

Resistance to cetuximab is associated with specific RAS mutations. The RAS family of oncogenes includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells. The KRAS mutations are particularly common, being detectable in 40% of metastatic colorectal tumors.

The KRAS mutations often lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and are associated with resistance to anti-EGFR drugs such as cetuximab. In addition, mutations in NRAS and another gene, BRAF, have been associated with poor response to anti-EGFR therapy; however, BRAF mutation does not explicitly preclude anti-EGFR therapy. Combination therapies targeting both BRAF and EGFR have shown to improve survival for individuals with wild-type RAS and mutant BRAF.

The 2018 FDA-approved drug label for cetuximab states that for mCRC, cetuximab is indicated for K- and N-RAS wild-type (no mutation), EGFR-expressing tumors. The label states that an FDA-approved test must be used to confirm the absence of a RAS mutation (in either KRAS or NRAS) prior to starting cetuximab (Table 1) (1). While the FDA label also states that EGFR expression should also be confirmed by an approved test prior to starting therapy for mCRC, this is largely not implemented in practice, nor is it recommended by professional oncology society guidelines.

Similarly, the 2015 Update from the American Society of Clinical Oncology (ASCO) states that anti-EGFR therapy should only be considered for the treatment of individuals whose tumor is determined to not have mutations detected after extended RAS testing (Table 2) (2).

The 2020 National Comprehensive Cancer Network (NCCN) guideline also strongly recommends KRAS/NRAS genotyping of tumor tissue in all individuals with mCRC. In addition, the guideline states the V600E mutation in the BRAF gene makes a response to cetuximab (and panitumumab) highly unlikely unless given a BRAF inhibitor (Table 3) (3).

Drug: Cetuximab

Cetuximab is an EGFR antagonist. It is used for the treatment of mCRC, and squamous cell carcinoma of the head and neck. Cetuximab, and the related drug panitumumab (brand name Vectibix, approved only for mCRC), are monoclonal antibodies that specifically target the extracellular domain of EGFR. They act by blocking endogenous ligand binding to the extracellular domain of EGFR, and by enhancing receptor internalization and degradation (4). Cetuximab has also been used for off-label indications that include non-small cell lung cancer (5), squamous cell carcinoma of the skin (6), and Menetrier’s disease (7).

Cetuximab is a chimeric monoclonal antibody composed of regions of both mouse and human antibody, whereas panitumumab is a fully human monoclonal antibody. Both biological agents have been shown to provide a clear clinical benefit in the treatment of RAS wild-type mCRC (8, 9).

Colorectal cancer is the third leading cause of cancer death for men and women in the US, and the second in Europe (10). Radiation therapy is generally used for early stage rectal cancer. Surgery is the most common treatment for localized colorectal cancer that has not spread, and chemotherapy is given before (neoadjuvant) or after (adjuvant) surgery to most individuals with cancer that has penetrated the bowel wall deeply or spread to the lymph nodes (11).

Treatment regimens for advanced or metastatic colorectal carcinoma include chemotherapy such as folinic acid, fluorouracil, irinotecan, capecitabine, and oxaliplatin. Targeted biological agents may be added to such regimens, such as cetuximab, panitumumab, and bevacizumab. Bevacizumab (brand name Avastin) is a monoclonal antibody that targets vascular endothelial growth factor, VEGF. Similar FDA-approved biologics include aflibercept (a VEGF inhibitor monoclonal antibody) and regorafenib (a receptor tyrosine kinase inhibitor with activity against VEGF receptors).

Cetuximab is used in combination with FOLFIRI (FOLinic acid, Fluorouracil, IRInotecan) or FOLFOX (FOLinic acid, Fluorouracil, Oxaliplatin) for first-line treatment; or in combination with irinotecan in individuals who are refractory to irinotecan-based chemotherapy (1, 12). Cetuximab may also be used as a single agent (monotherapy) in individuals who either did not respond to oxaliplatin- and irinotecan-based chemotherapy or are intolerant to irinotecan (3).

Interestingly, the location of the primary colorectal tumor is a predictor of the prognosis for metastatic disease. Left-sided tumors derive from the embryonic hindgut (which gives rise to the splenic flexure, descending colon, sigmoid colon, rectum, and one-third of the transverse colon). Whereas right-sided tumors derive from the embryonic midgut (which gives rise to the appendix, cecum, ascending colon, hepatic flexure, and two-thirds of the transverse colon) (13). These differences in embryologic origin correlate with common genetic alterations. Right-sided tumors are more likely to have mutated RAS and BRAF, while left-sided tumors may have upregulated EGFR and/or ERBB2 (HER2) (14). Thus, individuals with left-sided tumors benefit more from EGFR therapy than individuals with right-sided tumors (15, 16, 17).

Multiple professional guidelines suggest that cetuximab has limited benefit in first-line therapy for right-sided tumors (18, 19). Right-sided tumors may respond to bevacizumab in combination with chemotherapy, with potentially longer overall survival compared with cetuximab combination treatment (15, 16, 20). A recent review highlighted multiple retrospective studies regarding the prognostic and predictive power of right- versus left-sidedness of the primary tumor. The authors concluded that in first-line treatment, left-sided tumors were distinctly more likely to respond to anti-EGFR treatment. However, there was no clear consensus for the implications of tumor sidedness with respect to second-line (and beyond) treatment. (21)

Administration of IV anti-EGFR therapy may be associated with severe infusion reactions, including anaphylaxis (3% for cetuximab and 1% for panitumumab) and these reactions are more common in cetuximab treatment versus panitumumab (22). Other toxicities include cardiopulmonary arrest, severe skin rashes (the severity of which may predict an increased response and survival, regardless of RAS mutational status (23, 24)), and an increased risk of venous thrombosis and embolism (2, 11, 25). Additionally, a higher rate of cetuximab-induced infusion reactions has been reported in head and neck cancer treatment (5.4%) as compared with mCRC treatment (26). Within the United States, there appears to be a higher risk of anaphylaxis reaction in areas of the Southeast including North Carolina, Virginia, Tennessee, Florida as well as Missouri and Kansas (reviewed by (27)). Evidence suggests these infusion reactions are due to the presence of immunoglobulin E antibodies targeting a specific glycosylation moiety found on cetuximab (28). The presence of these antibodies in cetuximab-naïve individuals may be due to prior bites from the lone star tick (Amblyomma americanum) (29).

Cetuximab can cause fetal harm when administered during pregnancy. There are no studies in pregnant women, but in animal studies (cynomolgus monkeys) the administration of IV cetuximab in pregnancy resulted in an increased risk of fetal death. Women should be advised to use effective contraception during cetuximab therapy and for 2 months after the last dose. Women should also be advised of the potential risks to the fetus, and to inform their healthcare provider if they know or suspect they are pregnant.

An important role in the progression of mCRC is thought to involve the impaired regulation of EGFR function, resulting in activation of the associated MAPK pathway. Cetuximab and panitumumab are important agents in metastatic disease because they can block the activation of the MAPK pathway. However, resistance to these agents can arise through constitutive activation of the MAPK pathway, which is caused by mutations in downstream signaling proteins, such as KRAS, NRAS and BRAF. Approximately 40% of cases of mCRC are found to have activating mutations in KRAS.

The efficacy of cetuximab in treating mCRC is confined to individuals with wild-type KRAS tumors. Specifically, tumors that do not harbor specific mutations in exons 2, 3, and 4 of the KRAS gene. The NRAS gene is highly similar (homologous) to KRAS, and mutations in the same exons—2, 3, and 4—are also associated with a lack of response to cetuximab (17, 30, 31, 32, 33).

Therefore, expanded RAS testing (of KRAS and NRAS) is the standard of care to determine which individuals with mCRC may benefit from anti-EGFR therapy (34, 35).

Epidermal growth factor receptor overexpression is seen commonly in squamous cell head and neck cancers and is associated with poor survival outcomes (36, 37). Trials with cetuximab in local or metastatic head and neck cancers have shown this anti-EGFR therapy to have most benefit as part of combination therapies in metastatic cancer, with limited application in local, unresectable disease (reviewed by (18)). Neither the FDA-approved drug label nor NCCN guidelines recommend RAS genetic testing before initiating therapy with cetuximab in head and neck cancers (1, 18).

Proto-oncogenes

Proto-oncogenes are a group of genes that, when mutated or expressed at abnormally high levels, can contribute to normal cells becoming cancerous cells. The mutated version of the proto-oncogene is called an oncogene.

Proto-oncogenes typically encode proteins that stimulate cell division, inhibit cell differentiation, and halt cell death. All these are important biological processes; however, the increased production of these proteins, caused by oncogenes, can lead to the proliferation of poorly differentiated cancer cells (11). Members of the RAS family and the EGFR gene are all proto-oncogenes.

The RAS family contains three genes, HRAS, NRAS, and KRAS, and they are essential components of signaling pathways. They act as signal transducers –– coupling cell surface receptors to intracellular signaling pathways.

The RAS proteins regulate cell signal transduction by acting as a switch –– they cycle between "on" (GTP-bound) or "off" (GDP-bound) conformations. In the "on" position, RAS proteins transmit extracellular growth signals to the nucleus, primarily by the MAPK pathway. Cells are subsequently stimulated to grow, divide, mature, and differentiate.

Mutations in RAS genes leads to RAS proteins that are resistant to GTPase, so that GTP-remains permanently bound and the receptor remains "on" –– providing a continual growth stimulus to cells. Such activating RAS mutations are common in colorectal cancers.

The EGFR gene is a member of the human epidermal growth factor receptors family (HER) along with ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). Overexpression of these genes has been associated with multiple cancer types. These receptors dimerize upon binding of an extracellular ligand and activate the downstream signaling pathways, including Ras/Raf/Mek/Erk proteins. In some contexts, overexpression of HER2 can promote dimerization without an extracellular signal, leading to constitutive activation. (38, 39)

Gene: KRAS

KRAS is the most frequently mutated RAS gene found in metastatic colorectal carcinoma. The most frequent individual mutations occur in KRAS exon 2, in codons 12 (G12D, G12V) and 13 (G13D). Collectively, these mutations account for 40% of all RAS mutations in mCRC (40). Individuals with mCRC that harbor KRAS mutations do not benefit from anti–EGFR therapy (either cetuximab or panitumumab therapy) (3, 41, 42, 43, 44, 45, 46).

Gene: NRAS

NRAS is highly homologous to KRAS, and mutations have been reported in exons 2, 3, and 4. Although NRAS mutations are not as frequent as KRAS in mCRC, occurring in approximately 2% of tumors, NRAS influences the response to treatment with anti-EGFR drugs (2, 47, 48, 49).

Individuals with NRAS-mutated tumors are less likely to respond to cetuximab or panitumumab (19, 25). Panitumumab may even have a detrimental effect in individuals with NRAS or KRAS mutations (2).

Gene: BRAF

RAF is a family of serine/threonine kinases that are downstream effectors of KRAS, within the MAPK signaling pathway. The RAF family has 3 members, ARAF, BRAF and CRAF (50).

BRAF mutations are detectable in approximately 5–15% of mCRCs. They tend to only occur in tumors that do not have KRAS exon 2 mutations (51). It is therefore unlikely that tumors with KRAS mutations will respond to either anti-BRAF treatment (which targets mutant BRAF) or anti-EGFR treatment (because of the presence of KRAS mutations) (52).

By far the most common BRAF mutation is known as V600E, which accounts for approximately 90% of BRAF mutations. The mutated BRAF protein is constitutively active and is a highly potent oncogene, acting downstream in the EGFR pathway, thus bypassing inhibition of EGFR by cetuximab or panitumumab (10). Constitutively active BRAF can then activate the downstream kinases MEK1 and MEK2, which ultimately activate ERK kinases at the terminus of the MAP kinase signaling pathway (53).

The BRAF V600E mutation is associated with a poorer prognosis for individuals with mCRC, as well as with resistance to anti-EGFR treatment. It is also possible that other BRAF mutations contribute to anti-EGFR resistance. In BRAF V600E-mutant mCRC, BRAF inhibition results in rapid feedback activation of EGFR, a likely mechanistic explanation for limited clinical utility of this monotherapy (54). Alternative treatments may include the use of drug combinations, such as the addition of a BRAF inhibitor to anti-EGFR, to overcome resistance (35, 55). Indeed, utilization of BRAF inhibitor therapy in combination with anti-EGFR (with or without additional targeting of MEK kinases) showed improved survival in the BEACON trial, with the greatest overall survival in the group targeting BRAF, EGFR and MEK simultaneously (54, 56). Guidelines from the NCCN recommend this triple therapy as one approach for BRAF V600E mutation-positive disease (3). The NCCN guidelines recommend additional combination therapies for BRAF V600E positive colorectal cancer of either vemurafenib, irinotecan and anti-EGFR monoclonal antibodies (cetuximab or panitumumab) or dabrafenib, trametinib and anti-EGFR monoclonal antibodies (3).

The NCCN Colon/Rectal Cancer Panel states that evidence increasingly suggests that the BRAF V600E variant makes response to panitumumab or cetuximab, as single agents or in combination with cytotoxic chemotherapy, highly unlikely unless it is also given with a BRAF inhibitor. Therefore, the panel recommends BRAF genotyping of tumor tissue (either primary tumor or metastasis) at diagnosis of stage IV disease (3).

Gene: EGFR

The HER family consists of 4 members: ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). All 4 members are transmembrane tyrosine kinase receptors, and they regulate a number of important cellular processes, such as cell growth, survival, and differentiation.

The EGFR protein is expressed in many different tissues, and is activated by the binding of a ligand, such as epithelial growth factor (EGF) or transforming growth factor α (TGFα). Binding induces receptor dimerization, either homodimers or heterodimers with other HER family members, and triggers autophosphorylation of the intracellular tyrosine kinase domain.

By activating downstream signaling pathways, EGFR has many different biological roles, including stimulating the cell cycle, cell growth, division, differentiation, as well as increased cell invasiveness, apoptosis, and angiogenesis. Therefore, overexpression of EGFR is thought to be an important step in tumor progression, making EGFR a target for anticancer drugs (57, 58, 59).

Currently, there are 2 classes of drug that target EGFR: tyrosine kinase inhibitors (for example, gefitinib and erlotinib) and anti-EGFR monoclonal antibodies (for example, cetuximab and panitumumab) (4).

The EGFR protein is overexpressed in several cancers, including squamous cell carcinoma of the head and neck, squamous cell lung cancer, and colorectal cancer. The EGFR protein is overexpressed in approximately 50–80% of colorectal tumors (2, 60). The FDA-approved drug label for cetuximab states that the drug is licensed for EGFR-expressing mCRC, and mentions in animal studies using human tumor xenografts that lacked EGFR expression, that no anti-tumor effects of cetuximab were observed (1). However, for colorectal cancer, EGFR expression has not been associated with efficacy of anti-EGFR therapy (61).

The NCCN Colon/Rectal Cancer Panel states that EGFR testing of colorectal tumor cells has no proven predictive value in determining likelihood of response to either cetuximab or panitumumab. Therefore, the panel does not recommend routine EGFR testing, and states that no individual should be considered for, or excluded from, cetuximab or panitumumab therapy based on EGFR test results (3).

Gene: ERBB2 / HER2

HER2 belongs to the same family of signaling kinase receptors as EGFR and is encoded by the gene ERBB2, also called HER2. Monoclonal antibodies that target HER2, such as pertuzumab and trastuzumab, are used in the treatment of breast cancer. However, HER2 is rarely expressed in colorectal tumors (approximately 3% overall), though the prevalence is higher in RAS/BRAF wild-type tumors (5–14%) (3). Initial evidence suggested that HER2 overexpression may be predictive of resistance to anti-EGFR therapy, yet some evidence suggested that HER2 status is not a biomarker for cetuximab response (35, 62) A recent review of HER2 retrospective studies found a consistent correlation between ERBB2 amplification and resistance to anti-EGFR treatment (38).

The NCCN Colon/Rectal Cancer Panel recommends ERBB2 amplification/overexpression testing for individuals with mCRC. However, if the tumor is known to have a RAS or BRAF mutation, ERBB2 testing is not required. Based on the outcome of HER2 expression testing, the individual may be eligible for enrollment in one of the on-going clinical trials investigating targeted HER2 therapy in mCRC.(3) The NCCN guidelines emphasize that HER2 overexpression is not prognostic, but can be used to predict success of HER2-targeted therapy and resistance to anti-EGFR antibodies, including cetuximab (3). A dual tyrosine kinase inhibitor targeting HER2 and EGFR called lapatinib is also available and can be used in combination with anti-HER2 monoclonal antibodies for ERBB2-amplified mCRC (3).

Linking gene variation with treatment response

It has been established that specific variants in the genes KRAS and NRAS result in resistance to cetuximab therapy. In addition, the presence of the BRAF V600E mutation makes a beneficial response to treatment unlikely, unless given with a BRAF inhibitor (3, 56, 63). Specific point-mutation variants in ERBB2 and EGFR do not appear to be associated with cetuximab resistance. However, ERBB2 overexpression has been associated with decreased success of anti-EGFR therapies (38, 39).

Genetic Testing

The NIH Genetic Testing Registry, GTR, displays genetic tests that are available for the cetuximab drug response, and the genes KRAS, NRAS, EGFR, BRAF and ERBB2.

The 2020 NCCN Guideline for Colon Cancer (Version 4.2020) provides the following recommendations for genetic testing:

KRAS, NRAS, and BRAF Mutation and HER2 Testing

• All [individuals] with metastatic colorectal cancer should have tumor tissue genotyped for RAS (KRAS and NRAS) and BRAF mutations. [Individuals] with any known KRAS mutation (exon 2, 3, 4) or NRAS mutation (exon 2, 3, 4) should not be treated with either cetuximab or panitumumab. BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor. WT RAS/BRAF tumors should also be screened for HER2 overexpression/amplification.
• No specific methodology is recommended (e.g., sequencing, hybridization) for testing KRAS, NRAS, and BRAF mutations.
• The testing can be performed on formalin-fixed paraffin-embedded tissue. The testing can be performed on the primary colorectal cancers and/or the metastasis, as literature has shown that the KRAS, NRAS, and BRAF mutations are similar in both specimen types.

Microsatellite Instability (MSI) or Mismatch Repair (MMR) Testing

• Universal MMR* or MSI* testing is recommended in all newly diagnosed [individuals] with colon cancer. See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal (*IHC for MMR and DNA analysis for MSI are different assays and measure different biological effects caused by deficient MMR function)
• The presence of a BRAF V600E mutation in the setting of MLH1 absence would preclude the diagnosis of Lynch syndrome (LS) in the vast majority of cases. However, approximately 1% of cancers with BRAF V600E mutation (and loss of MLH-1) are LS. Caution should be exercised in excluding cases with a strong family history from germline screening in the case of BRAF V600E mutations
• Stage II MSI-H [individuals] may have a good prognosis […]
• Testing for MSI may be accomplished with a validated NGS panel, especially in [individuals] with metastatic disease who require genotyping of RAS and BRAF (3).

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

Allele Nomenclature

Acknowledgments

The authors would like to thank Carmen J. Allegra, MD, Professor of Medicine, University of Florida Health, Gainesville, FLA, USA; Thomas M. Delate, PhD, MS, Clinical Pharmacy Research Scientist, Drug Use Management, Kaiser Permanente National Pharmacy, Clinical Instructor, Clinical Pharmacy Department, Associate Member of University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Jared Freml, PharmD, Pharmacy Department, Kaiser Permanente Colorado, Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy & Pharmaceutical Sciences, Aurora, CO, USA; and Jesus Hermosillo-Rodriguez, MD, Oncology Department, Colorado Permanente Medical Group, Denver, CO, USA for reviewing this summary.

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