Medical Policy: 02.04.20
Original Effective Date: October 2008
Reviewed: January 2021
Revised: January 2021
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Cetuximab (Erbitux®, ImClone Systems) and panitumumab (Vectibix®, Amgen) are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing intrinsic ligand binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization. Some individuals with colorectal cancer have tumors with a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation that may affect tumor response to these EGFR inhibitors.
The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. RAS proteins are G-proteins that cycle between active (RAS-GTP) and inactive (RAS-GDP) forms, in response to stimulation from a cell surface receptor such as EGFR, and act as a binary switch between the cell surface EGFR and downstream signaling pathways. The KRAS gene can harbor oncogenic mutations that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. KRAS mutations are found in approximately 30-50% of colorectal cancer tumors and are common in other tumor types. KRAS and BRAF mutations are considered to be mutually exclusive.
Cetuximab and panitumumab are approved in the treatment of metastatic colorectal cancer (mCRC) and anal adenocarcinoma in the setting of refractory disease. Data from randomized controlled trials have consistently shown a lack of clinical response to cetuximab and panitumumab in patients with mutated KRAS, with tumor response and prolongation of progression-free survival observed only in patients with wild-type KRAS mutations.
KRAS mutation analysis using polymerase-chain reaction (PCR) methods is commercially available as a laboratory-developed test in a CLIA-licensed laboratory.
Clinical trial data show that patients with KRAS-mutated metastatic colorectal cancer do not benefit from cetuximab (Erbitux®) or panitumumab (Vectibix®) when given in combination with other treatment regimens or when used alone.
Another RAS gene is the neuroblastoma RAS viral (v-ras) oncogene homolog, or (NRAS). NRAS mutations are found in 2-7% of CRCs and occur most commonly in codon 61 rather than codon 12 or 13. NRAS mutations are mutually exclusive from KRAS and NRAS mutation testing should be performed when KRAS is wild-type. The presence of NRAS mutations is associated with lack of response to cetuximab therapy.
NRAS, another member of the RAS family of protooncogenes, which can harbor mutations in codons 12, 13, and 61. Thus, the NRAS oncogene also may have an impact on outcomes of anti-EGFR treatments for CRC. Compared with KRAS, NRAS mutations are extremely rare. Although NRAS mutations account for approximately 15% of all RAS mutations, they are found in perhaps 2% to 7% of all CRC.
BRAF (also known as serine/threonine-protein kinase B-Raf, v-raf murine sarcoma viral oncogene homolog B1) encodes a protein kinase which is implicated in intracellular signaling and cell growth and is a direct downstream effector of KRAS.
The presence of the V600E BRAF mutation in tumors is associated with a poor prognosis in colorectal cancer, colon cancer, and several other cancer types. V600E BRAF mutation is linked to a poor response to anti-EGFR therapies and shorter survival independent of anti-EGFR therapies. The published literature does not yet clearly define the role of BRAF status in response to EGFR inhibitor therapy. It is still unclear to what extent the lack of response in individuals with KRAS wild-type is solely due to BRAF mutations. The determination of BRAF mutation analysis within the NCCN guidelines in 2016 for colon and rectal cancer is the first step in the treatment algorithm.
There are no FDA-approved targeted therapies for BRAF V600 variant-positive glioma.
The EGFR signaling system is quite complex which may explain the modest objective response rates that have been achieved with clinical trials of EGFR inhibitors to date, as well as the disparities observed between clinical and preclinical findings. Metastatic colorectal predictive algorithms to identify additional patients with metastatic colorectal cancer who are unlikely to respond to treatment with an EGFR-targeted monoclonal antibody are being developed. These algorithms include the addition of BRAF, expression to NRAS/KRAS analysis. BRAF testing is included in the NCCN guidelines under principles of pathologic review.
It is uncertain whether the presence of a BRAF V600 variant in patients with metastatic colorectal cancer who are wild-type on KRAS and NRAS variant analysis is predictive of response to anti-epidermal growth factor receptor therapy. Furthermore, there is mixed opinion in clinical guidelines and clinical input on the use of BRAF variant analysis to predict response to treatment.
In 2017, vemurafenib (Zelboraf) was approved by the FDA for Erdheim-Chester disease with BRAFV600 mutation. Zelboraf is the first FDA-approved treatment for Erdheim-Chester disease (ECD), a rare blood disease. The need to obtain BRAF mutation analysis prior to the planned treatment with vemurafenib in Erdheim-Chester disease is essential in the treatment planning process.
The National Comprehensive Cancer Network (NCCN) guidelines (v2.2021) on the treatment of colon cancer, and the guideline on rectal cancer (v1.2021) recommend that tumor KRAS, NRAS, and BRAF gene status testing be performed for all patients with metastatic colorectal cancer. Testing should be performed on archived specimens of primary tumor or a metastasis at the time of diagnosis of metastatic disease. The guidelines indicate that cetuximab and panitumumab are appropriate only for patients with tumor that expresses the WT KRAS gene. Abnormal MLH1 should be followed by tumor testing for BRAF V600E mutation. BRAF V600E mutation makes response to cetuximab and panitumumab highly unlikely.
The National Comprehensive Cancer Network (NCCN) guidelines (v2.2020) on anal cancer discusses the use of cetuximab in anal cancer as a promising avenue of investigation. The need for KRAS/NRAS testing is essential in determining effectiveness of an EGFR inhibitor such as cetuximab. KRAS mutations appear to be very rare in anal cancer.
In 2015 the National Comprehensive Cancer Network (NCCN) guidelines for both colon and rectal cancer were updated to include the addition of RAS mutation analysis which includes both KRAS and NRAS gene testing in the workup for all patients with metastatic colorectal cancer. The guidelines state that cetuximab and panitumumab are only indicated for patients with tumors that express the wild-type KRAS/NRAS gene. BRAF was added to the recommendation in the 2019 update for colon and rectal cancers.
National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma, version 1.2021, recommend BRAF mutation testing is recommended for patients being considered for adjuvent therapy with stage III melanoma for whom future BRAF-directed therapy may be an option. In general, uveal melanoma (Version 3.2020) rarely have BRAF mutations.
National Comprehensive Cancer Network (Version 1.2021) guideline recommends that BRAF testing (category 2A) be performed in the workup of B-Cell Lymphomas, with certain molecular characteristics.
The need for KRAS/NRAS or BRAF testing is not identified in the guidelines for workup (initial or recurrence). There is an increased occurrence of KRAS mutation, but the need for testing is not necessary for treatment decisions of SBA at this time. In regimens not recommended: NCCN states that cetuximab or panitumumab should not be used for SBA.
The need for BRAF testing is identified in the latest guideline for workup on adjuvant therapy selection. Mutation status would identify those who would benefit from treatment with an FDA-approved BRAF inhibitor.
The International Association for the Study of Lung Cancer and the Association for Molecular Pathology published evidence-based guidelines addressing molecular testing to select individuals with lung cancer for treatment with EGFR and alkaline phosphatase TKI therapy. Based on a category B rating (good quality evidence), the authors do not recommend KRAS mutation testing as a sole determinant of EGFR TKI therapy. The guideline states: The significance of KRAS mutational analysis may become increasingly important with the further development of new therapies targeting downstream RAS pathways, such as PI3K/AKT/mTOR and RAS/RAF/MEK, but at this time, the absence of a KRAS mutation does not add clinically useful information to the EGFR mutation result and should not be used as a determinant of EGFR TKI therapy.
Summary of recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.
The EWG found insufficient evidence to recommend for or against BRAF V600E testing for the same clinical scenario. The level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low.
Colorectal carcinoma patients being considered for anti-epidermal growth factor receptor (EGFR) therapy must receive RAS (rat sarcoma viral oncogene homolog) mutational testing. Mutational analysis should include KRAS (Kirsten rat sarcoma viral oncogene homolog) and NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) codons 12, 13 of exon 2; 59, 61 of exon 3; and 117 and 146 of exon 4 ("expanded" or "extended" RAS) (Type: recommendation; Strength of Evidence: convincing/adequate, benefits outweigh harms; Quality of Evidence: high/intermediate).
BRAF (V-raf murine sarcoma viral oncogene homolog B1) p.V600 (BRAF c. 1799 [p.V600]) position mutational status is recommended for prognostic stratification in selected patients with CRC (Recommendation 2a) and that there is insufficient evidence to recommend BRAF pV600 mutational status as a predictive molecular biomarker for response to anti-EGFR inhibitors (Recommendation 4).
BRAF p.V600 mutational analysis should be performed in deficient mismatch repair (MMR) tumors with loss of MLH1 (MutL homolog 1) to evaluate for Lynch syndrome risk. Presence of a BRAF mutation strongly favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome (Type: recommendation; Strength of Evidence: adequate/inadequate, balance of benefits and harms; Quality of Evidence: intermediate/low).
Companion diagnostic tests for the selection of cetuximab and panitumumab have been approved by the FDA through the premarket approval process.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. KRAS, NRAS, and BRAF variant analyses using polymerase chain reaction methodology are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test. No liquid biopsy test is currently FDA approved to select treatment for patients with metastatic colorectal cancer.
See related policies:
KRAS, NRAS, and BRAF V600E mutation tumor analysis may be considered medically necessary to predict nonresponse to cetuximab and panitumumab in the treatment of metastatic (Stage IV) colorectal cancer. Testing must be done prior to initiation of therapy.
Analysis of KRAS and NRAS status is considered medically necessary to predict treatment response to the anti-EGFR monoclonal antibody cetuximab (Erbitux), or panitumumab (Vectibix) in individuals with anal adenocarcinoma prior to initiation of cetuximab or panitumumab.
BRAF sequencing may be considered medically necessary in confirming mutant protein in small cell neoplasms.
BRAF V600E mutation analysis is considered medically necessary to distinguish variant from classical hairy cell leukemia in relapsed disease.
BRAF mutation analysis with a diagnosis of stage III or IV (metastatic or unresectable) metastatic melanoma to predict nonresponse to vemurafenib, dabrafenib, or trametinib may be considered medically necessary. Testing must be completed prior to initiation of therapy.
BRAF mutation analysis is considered medically necessary to determine adjuvant treatment decisions in gliomas (including the following pathology: astrocytomas, xanthoastrocytomas, gangliogiomas)
BRAF mutation analysis with a diagnosis of Erdheim-Chester to predict nonresponse to vemurafenib, may be considered medically necessary. Testing must be completed prior to initiation of therapy.
BRAF mutation analysis with a diagnosis of Gastrointestinal Stromal Tumors (GIST) to predict nonresponse to imatinib, may be considered medically necessary. Testing must be completed prior to initiation of therapy.
KRAS, NRAS or BRAF mutation analysis for all other indications, including but not limited to the following, is considered investigational:
KRAS, NRAS, or BRAF is considered investigational for routine testing at initial diagnosis.
Test miR-31now™ (GoPath Laboratories) is considered not medically necessary. The use of theranostic testing has not been proven to positively impact treatment regimen decisions with improved outcomes at this time.
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