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Panitumumab response

Synonyms
Vectibix response

Summary

Panitumumab 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. 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. 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. 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. 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. [from Medical Genetics Summaries]

Available tests

2 tests are in the database for this condition.

Clinical tests (2 available)

Biochemical Genetics Tests

Molecular Genetics Tests

Genes See tests for all associated and related genes

  • Also known as: B-RAF1, B-raf, BRAF-1, BRAF1, NS7, RAFB1, BRAF
    Summary: B-Raf proto-oncogene, serine/threonine kinase

  • Also known as: ERBB, ERBB1, ERRP, HER1, NISBD2, PIG61, mENA, EGFR
    Summary: epidermal growth factor receptor

  • Also known as: CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19, NEU, NGL, TKR1, VSCN2, c-ERB-2, c-ERB2, p185(erbB2), ERBB2
    Summary: erb-b2 receptor tyrosine kinase 2

  • Also known as: 'C-K-RAS, C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B, K-Ras, K-Ras 2, KI-RAS, KRAS1, KRAS2, NS, NS3, OES, RALD, RASK2, c-Ki-ras, c-Ki-ras2, KRAS
    Summary: KRAS proto-oncogene, GTPase

  • Also known as: ALPS4, CMNS, KRAS, N-ras, NCMS, NRAS1, NS6, NRAS
    Summary: NRAS proto-oncogene, GTPase

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted1information 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)

2020 Clinical Practice Guidelines in Oncology: Colon Cancer, from the National Comprehensive Cancer Network (NCCN)

Version 4.2020 – Discussion update in progress.

A sizable body of literature has shown that tumors with a mutation in codon 12 or 13 of exon 2 of the KRAS gene are essentially insensitive to cetuximab or panitumumab therapy. More recent evidence shows mutations in KRAS outside of exon 2 and mutations in NRAS are also predictive for a lack of benefit to cetuximab and panitumumab.

The panel therefore strongly recommends RAS (KRAS/NRAS) genotyping of tumor tissue (either primary tumor or metastasis) in all individuals with metastatic colorectal cancer. Individuals with known KRAS or NRAS mutations should not be treated with either cetuximab or panitumumab, either alone or in combination with other anticancer agents, because they have virtually no chance of benefit and the exposure to toxicity and expense cannot be justified. It is implied throughout the guidelines that NCCN recommendations involving cetuximab or panitumumab relate only to individuals with disease characterized by KRAS/NRAS wild-type genes. ASCO released a Provisional Clinical Opinion Update on extended RAS testing in individuals with metastatic colorectal cancer that is consistent with the NCCN panel’s recommendations. A guideline on molecular biomarkers for colorectal cancer developed by the ASCP, CAP, AMP and ASCO also recommends RAS testing consistent with the NCCN recommendations.

The recommendation for KRAS/NRAS testing, at this point, is not meant to indicate a preference regarding regimen selection in the first-line setting. Rather, this early establishment of KRAS/NRAS status is appropriate to plan for the treatment continuum, so that the information may be obtained in a non- time–sensitive manner and the individual and provider can discuss the implications of a KRAS/NRAS mutation, if present, while other treatment options still exist. Note that because anti-EGFR agents have no role in the management of stage I, II, or III disease, KRAS/NRAS genotyping of colorectal cancers at these earlier stages is not recommended. […] The NCCN Colon/Rectal Cancer Panel believes that RAS mutation status should be determined at diagnosis of stage IV disease. Individuals with any known RAS mutation should not be treated with either cetuximab or panitumumab.

KRAS mutations are early events in colorectal cancer formation, and therefore a very tight correlation exists between mutation status in the primary tumor and the metastases. For this reason, KRAS/NRAS genotyping can be performed on archived specimens of either the primary tumor or a metastasis. Fresh biopsies should not be obtained solely for the purpose of KRAS/NRAS genotyping unless an archived specimen from either the primary tumor or a metastasis is unavailable.

Approximately 5% to 9% of colorectal cancers are characterized by a specific mutation in the BRAF gene (V600E). BRAF mutations are, for all practical purposes, limited to tumors that do not have KRAS exon 2 mutations. Activation of the protein product of the non-mutated BRAF gene occurs downstream of the activated KRAS protein in the EGFR pathway. The mutated BRAF protein product is believed to be constitutively active, thereby putatively bypassing inhibition of EGFR by cetuximab or panitumumab.

The panel recommends that KRAS, NRAS, and BRAF gene testing be performed only in laboratories that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88) as qualified to perform highly complex molecular pathology testing. No specific testing methodology is recommended.

Please review the complete therapeutic recommendations that are located here:(3)

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug.

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