Panitumumab Therapy and RAS and BRAF Genotype

Introduction

Panitumumab (brand name Vectibix) is a monoclonal antibody used for the treatment of metastatic colorectal cancer (mCRC). Panitumumab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered every 14 days as an intravenous (IV) infusion, often with chemotherapy. Panitumumab is approved for first-line therapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy (1).

The location of the primary tumor correlates whether an individual with mCRC is likely respond to anti-EGFR therapy. 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, only the genetic variation status of the tumor, and not the location of the tumor, is discussed in the FDA drug label’s dosing recommendations.

Resistance to panitumumab is associated with specific RAS mutations. The RAS is a family of oncogenes that includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells by providing a continual growth stimulus to 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 EGFR and are associated with resistance to anti-EGFR drugs such as panitumumab. Mutations in NRAS and another gene, BRAF, have also been associated with poor response to anti-EGFR therapy.

The 2017 FDA-approved label states that panitumumab is indicated for wild-type RAS (no mutations in either KRAS or NRAS) mCRC (Table 1). The label states that an FDA-approved test must be used to confirm the absence of RAS mutations before starting panitumumab, and that panitumumab is not indicated for the treatment of individuals with colorectal cancer with RAS mutations (in either NRAS or KRAS), or when the RAS genetic variation status is unknown (1).

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 variations 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 panitumumab highly unlikely, unless given with a BRAF inhibitor (Table 3) (3).

Drug: Panitumumab

Panitumumab is an EGFR antagonist and is used for the treatment of mCRC. Panitumumab, and the related drug cetuximab (brand name Erbitux), 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).

Panitumumab is a fully human monoclonal antibody, whereas cetuximab a chimeric monoclonal antibody, being composed of regions of both murine and human antibody. Both drugs have been shown to provide a clear clinical benefit in the treatment of RAS wild-type mCRC (5, 6).

Colorectal cancer is the second leading cause of cancer death for men and women in the US, and the second in Europe (7, 8). Surgery is the most common treatment for localized colorectal cancer that has not spread. Chemotherapy alone, or with radiation, 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 (9). In the context of localized colon cancer, surgery first with adjuvant chemotherapy is standard. For localized rectal cancer, chemotherapy and chemoradiation can be used before or after surgery; standard therapy is either chemoradiation followed by surgery and adjuvant chemotherapy or chemoradiation and chemotherapy followed by surgery (10). National Comprehensive Cancer Network (NCCN) guidelines state there is a lack of definitive data or clear benefit from multiple types of adjuvant therapy for stage II or III colon cancer (3).

Treatment regimens for advanced or metastatic colorectal carcinoma include drugs such as folinic acid, fluorouracil, irinotecan, capecitabine, and oxaliplatin. Targeted biological agents may be added to such regimens, such as panitumumab, cetuximab, bevacizumab, ziv-aflibercept and ramucirumab. Bevacizumab (brand name Avastin) is a monoclonal antibody that targets vascular endothelial growth factor, VEGF. The NCCN guidelines provide further detail regarding which combinations are recommended based on tumor pathology (3).

Panitumumab is used with FOLFOX (FOLinic acid, Fluorouracil, and OXaliplatin) as a first-line treatment. It can also be combined with second-line chemotherapy (11). Additionally, it is used a single agent (monotherapy) following disease progression after chemotherapy including fluoropyrimidine, oxaliplatin, and irinotecan (with or without anti-VEGF therapy) (12, 13, 14, 15, 16). Although panitumumab is not indicated as first-line therapy in combination with irinotecan-based regimes, this may be an appropriate therapy for specific individuals (17, 18, 19). However, the NCCN advises against combining panitumumab with a bevacizumab-containing regimen due to inferior outcomes and toxicity (3, 20, 21).

Of note, 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) (22). The ASCO recommends that individuals with left-sided tumors versus right-sided tumors are more likely to receive benefit of anti-EGFR therapy in a first-line, maximal-resourced setting (23).

Individuals with left-sided tumors benefit more from EGFR therapy than individuals with right-sided tumors. Panitumumab appears to have no meaningful activity for right-sided tumors, except perhaps where early response and tumor shrinkage is an important indicator (24). Right-sided tumors may respond to bevacizumab (25, 26, 27, 28, 29).

Administration of intravenous anti-EGFR therapy is associated with severe infusion reactions, including anaphylaxis (1% for panitumumab and 3% for cetuximab). Others include cardiopulmonary arrest, severe skin rashes (the severity of which may predict an increased response and survival (30, 31)), and an increased risk of venous thrombosis and embolism (2, 9)

Pregnant women and females of childbearing age should be advised that panitumumab can cause fetal harm. Based on data from animal studies (cynomolgus monkeys), panitumumab can be lethal to embryos. Therefore, females of reproductive potential should use effective contraception during panitumumab therapy, and for at least 2 months after the last dose of panitumumab. Individuals who know or suspect they are pregnant should inform their healthcare provider.

An important role in the progression of mCRC is thought to involve the impaired regulation of EGFR function, resulting in activation of the associated mitogen-activated protein kinase (MAPK) pathway. Panitumumab and cetuximab are important drugs in metastatic disease because they can block the activation of the MAPK pathway. However, drug resistance can arise through constitutive activation of the MAPK pathway, caused by variation in downstream signaling proteins, such as KRAS, NRAS and BRAF. Approximately 40% of cases of mCRC are found to have activating mutations in KRAS (32, 33).

The efficacy of panitumumab 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 has mutations in the same exons—2, 3, and 4—which are also associated with a lack of response to panitumumab (33, 34, 35).

Therefore, expanded RAS testing (of KRAS and NRAS) is the standard of care to determine which individuals with mCRC will benefit from anti-EGFR therapy (36, 37).

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 (9). Members of the RAS family and the EGFR gene are all proto-oncogenes.

The RAS family contains 3 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.

Variation 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.

Gene: KRAS

The KRAS gene 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 more than 60% of all RAS mutations in mCRC (38). Individuals with mCRC that harbor KRAS mutations do not benefit from anti–EGFR therapy (either panitumumab or cetuximab therapy) (3, 5, 33, 34, 39).

Gene: NRAS

The NRAS gene 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, 40, 41, 42).

Individuals with NRAS-mutated tumors are less likely to respond to panitumumab or cetuximab (34, 39, 43). Furthermore, panitumumab may even have a detrimental effect in individuals with NRAS or KRAS mutations (2, 39) .

Gene: BRAF

The RAF proteins are 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 (44).

The BRAF mutations are detectable in approximately 5–15% of mCRC individuals. They tend to only occur in tumors that do not have KRAS exon 2 mutations (45). 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) (46).

By far the most common BRAF mutation is known as V600E, which accounts for approximately 90% of BRAF mutations. The resulting BRAF V600E protein is constitutively active and is a highly potent oncogene, acting downstream in the EGFR pathway, thus bypassing inhibition of EGFR by panitumumab or cetuximab (7). 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 (47).

The BRAF V600E mutation is associated with a poorer diagnosis 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 (48). Alternative treatments may include the use of drug combinations, such as the addition of a BRAF inhibitor to anti-EGFR, to overcome resistance (36, 49). Indeed, utilization of BRAF inhibitor therapy 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 (48, 50). 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 CRC 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 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 human epidermal growth factor receptor (HER) family consists of 4 members: the EGFR, 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 is expressed in many different tissues, and is activated by the binding of a ligand, such as epithelial growth factor or transforming growth factor α. 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 the EGFR a target for anticancer drugs (51, 52, 53).

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 is overexpressed in several cancers, including squamous cell carcinoma of the head and neck, squamous cell lung cancer, and colorectal cancer. The EGFR is overexpressed in approximately 50–80% of colorectal tumors (2, 51). However, for colorectal cancer, EGFR expression has not been associated with efficacy of anti-EGFR therapy (54).

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 panitumumab or cetuximab. 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: HER2/ERBB2

The HER2 receptor 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 anti-EGFR response (36, 55) A recent review of HER2 retrospective studies found a consistent correlation between HER2 amplification and resistance to anti-EGFR treatment (56).

The NCCN Colon/Rectal Cancer Panel recommends HER2 amplification/overexpression testing for individuals with mCRC. However, if the tumor is known to have a RAS or BRAF mutation, HER2 testing is not required. Based on the outcome of HER2 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 panitumumab (3).

Linking gene variation with treatment response

Specific mutations in the genes KRAS and NRAS result in resistance to panitumumab therapy. In addition, the presence of the BRAF V600E mutation makes a beneficial response to monotherapy treatment unlikely, combination therapy targeting BRAF and EGFR is recommended in these circumstances. Mutations in EGFR do not appear to be associated with panitumumab resistance. Initial results suggest HER2 amplification may predict resistance to panitumumab (reviewed in (3)).

Genetic Testing

The NIH Genetic Testing Registry, GTR, displays genetic tests that are available for the panitumumab drug response, and the genes KRAS, NRAS, BRAF, HER2, and EGFR

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

KRAS, NRAS, and BRAF Mutation Testing

• All [individuals] with metastatic colorectal cancer should have tumor tissue genotyped for RAS (KRAS and NRAS) and BRAF [variants] individually or as part of an NGS panel. [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.
• 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 by polymerase chain reaction or 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.

2017 Statement from the US Food and Drug Administration (FDA):

Prior to initiation of treatment with panitumumab, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in individuals with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics.

[…]

Panitumumab is not indicated for the treatment of individuals with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS”.

Please review the complete therapeutic recommendations that are located here: (1)

2015 Provisional Clinical Opinion from the American Society of Clinical Oncology (ASCO) and 2020 Late-Stage Colorectal Cancer ASCO Resource-Stratified Guidelines
All individuals with metastatic colorectal cancer who are candidates for anti-EGFR antibody therapy should have their tumor tested in a Clinical Laboratory Improvement Amendments–certified laboratory for mutations in both KRAS and NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146). The weight of current evidence indicates that anti-EGFR monoclonal antibody therapy should only be considered for treatment of individuals whose tumor is determined to not have mutations detected after such extended RAS testing.

What’s New and Different?

In addition to testing for mutations in KRAS exon 2 (codons 12 and 13) as recommended previously, before treatment with anti-EGFR antibody therapy, individuals with mCRC should have their tumor tested for mutations in:

• KRAS exons 3 (codons 59 and 61) and 4 (codons 117 and 146)
• NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146)

Targeted therapies such as anti-VEGF and anti-EGFR agents may be added to doublet chemotherapies in maximal settings. […] If molecular testing results for RAS (KRAS/NRAS) are available, this guideline provides recommendations according to the status of these markers. In maximal (-resource) settings, for individuals with left-sided colon cancer and known KRAS/NRAS wild type (WT) molecular status, anti-EGFR antibodies such as cetuximab or panitumumab may be added to chemotherapy doublet, with a moderate-strength recommendation. However, individuals with right-sided colon cancer and RAS WT status should not be offered treatment with anti-EGFR antibodies in the first-line setting. Anti-EGFR therapies have increased response rates and conversion from unresectable to resectable metastatic disease when added to chemotherapy with FOLFOC or FOLFIRI for individuals with RAS wildtype, but more recent data suggest that debenit with anti-EGFR therapies seems to be limited to individuals whose primary tumors are left-sided.

Please review the complete therapeutic recommendations that are located here: ( 2 , 23 )

Allele Nomenclature

Selected KRAS Somatic Variants

Table

NP_004976.2:p.Gly12Asp NM_004985.5:c.35G>T

Selected NRAS Somatic Variants

Table

Selected BRAF Somatic Variants

Table

Acknowledgments

The authors would like to thank Timothy Price, MBBS, DHlthSc (Medicine), FRACP, Head of Clinical Cancer Research and Medical Oncologist, The Queen Elizabeth Hospital Campus, CALHN, Woodville South, Adelaide, Australia; Benjamin A. Weinberg, MD, Assistant Professor of Medicine, Division of Hematology and Oncology, Attending Physician, MedStar Georgetown University Hospital, Gastrointestinal Medical Oncologist, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA; and Marc Peeters, MD, PhD, Head of Oncology, Coordinator of Multidisciplinary Oncology Center Antwerp, University Hospital Antwerp, Antwerp, Belgium for reviewing this summary.

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