Cetuximab response

2.2 Recommended Dosage for Colorectal Cancer (CRC)

Determine EGFR-expression status using FDA-approved tests prior to initiating treatment. Also confirm the absence of a Ras mutation prior to initiation of treatment with cetuximab. Information on FDA-approved tests for the detection of K-Ras mutations in patients with metastatic CRC is available at: http://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm301431.htm.

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5.7 Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras- Mutant mCRC

Cetuximab is not indicated for the treatment of patients with CRC 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 K-Ras or N- Ras and hereafter is referred to as “Ras” or when the Ras status is unknown.

Retrospective subset analyses of Ras-mutant and wild-type populations across several randomized clinical trials, including CRYSTAL, were conducted to investigate the role of Ras mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies. Use of cetuximab in patients with Ras mutations resulted in no clinical benefit with treatment related toxicity. Confirm Ras mutation status in tumor specimens prior to initiating cetuximab.

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

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 patients with metastatic colorectal cancer. Patients 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. ASCO released a Provisional Clinical Opinion Update on extended RAS testing in patients with metastatic colorectal cancer (mCRC) that is consistent with the NCCN panel’s recommendations. A guideline on molecular biomarkers for CRC developed by the ASCP, CAP, AMP and ASCO also recommends resting consistent with the NCCN recommendations.

The recommendation for RAS testing, at this point, is not meant to indicate a preference regarding regimen selection in the first-line setting. Rather, this early establishment of RAS status is appropriate to plan for the treatment continuum, so that the information may be obtained in a non- time–sensitive manner and the patient and provider can discuss the implications of a RAS 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, RAS genotyping of colorectal cancers at these earlier stages is not recommended.

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, RAS 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 RAS genotyping unless an archived specimen from either the primary tumor or a metastasis is unavailable.

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. The three genes can be tested individually or as part of an NGS panel.

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HER2 is a member of the same family of signalling kinase receptors as EGFR and has been successfully targeted in breast cancer in both the advanced and adjuvant settings. HER2 is rarely amplified/overexpressed in CRC (approximately 3% overall), but the prevalence is higher in RAF/BRAF-wild type tumors (reported at %5-14%). Specific molecular diagnostic methods have been proposed for HER2 testing in CRC and HER2-targeted therapies are now recommended as subsequent therapy options in patients with tumors that have HER2 overexpression. Based on this, the NCCN Guidelines recommend testing for HER2 amplifications for patients with mCRC. If the tumor is already known to have a KRAS/NRAS or BRAF mutations, HER2 testing is not required. As HER2-targeted therapies are still under investigation, enrollment in a clinical trial is encouraged.

Evidence does not support a prognostic role of HER2 overexpression. In addition to its role as a predictive marker for HER2-targeted therapy, initial results indicated HER2 amplification/overexpression may be predictive of resistance to EGFR-targeting monoclonal antibodies.

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

2015 Provisional Clinical Opinion from the American Society of Clinical Oncology (ASCO)All patients 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 MoAb therapy should only be considered for treatment of patients 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, patients 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)

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