Medical Policy: 02.04.20
Original Effective Date: October 2008
Reviewed: April 2015
Revised: April 2015
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
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.
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.
Cetuximab and panitumumab are approved in the treatment of metastatic colorectal cancer (mCRC) 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.
National Comprehensive Cancer Network (NCCN)
The National Comprehensive Cancer Network (NCCN) guidelines (v3.2015) on the treatment of colon cancer recommend that tumor KRAS gene status testing be performed for all patients with metastatic colon 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.
EGAPP (Evaluation of Genomic Applications in Practice and Prevention)
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.
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. Presently there is not enough evidence to determine the clinical utility of BRAF V600E mutation testing in patients with colon and colorectal cancers.
National Comprehensive Cancer Network (NCCN)
NCCN guidelines for colon cancer state that patients with a BRAF V600E mutation appear to have a poorer prognosis. However, evidence is insufficient to guide the use of anti-EGFR therapy in the first-line setting with active chemotherapy based on BRAF V600E mutation status.
National Comprehensive Cancer Network (NCCN) Guidelines for melanoma, version 3.2015, recommend vemurafenib, dabrafenib, and trametinib “only for patients with V600 mutation of the BRAF gene, as documented by an FDA-approved or CLIA-approved facility.” Vemurafenib and dabrafenib both have category 1 recommendations as preferred regimens for advanced or metastatic melanoma. Trametinib (monotherapy) has a category 1 recommendation as an “other active regimen.”
KRAS mutation analysis may be considered medically necessary to predict nonresponse to cetuximab and panitumumab in the treatment of metastatic colorectal cancer.
Testing for the BRAF V600E mutation may be considered not medically necessary to further stratify those patients with KRAS wild type tumors and to guide treatment for colorectal cancer. The management is unchanged with BRAF mutation knowledge.
BRAF mutation analysis with a diagnosis of stage IIIC or IV metastatic melanoma thatare being considered for treatment with vemurafenib, dabrafenib, or trametinib may be considered medically necessary.
KRAS or BRAF mutation analysis for all other indications is considered investigational.
Procedure Codes and Billing Guidelines:
To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
88363 Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis)
81275 KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene) (eg, carcinoma) gene analysis, variants in codons 12 and 13
81210 BRAF (v-raf murine sarcoma viral oncogene homolog B1) (eg, colon cancer), gene analysis, V600E variant
Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(10):1626-34.
Linardou H, Dahabreh IJ, Kanaloupiti D et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncology 2008 Sept 17. [Epub ahead of print].
Lievre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008; 26(3):374-9.
Van Cutsem E, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25(13):1658-64.
Khambata-Ford S, Garrett CR, Meropol NJ et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007; 25(22):3230-7.
Punt CJ, Tol J, Rodenburg CJ et al. Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 2008; 26(15 suppl); abstract LBA4011.
De Roock W, Piessevaux H, De Schutter J et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008 Mar;19(3):508-15. [E-pub 2007 Nov 12].
Peeters M, Balfour J, Arnold D. Review Article: Panitumumab- A fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer. Aliment Pharmacol Ther. 2008;28(3):269-81.
Amado RG, Wolf M, Peeters M et al. Wild-Type KRAS is required for Panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008 Apr 1; 26(10):1626-34.
Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer. N Engl J Med 2008 Oct 23;359 (17):1757-65.
Price TJ, Hardingham JE, Lee CK et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX Trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol 2011;29(19): 2675-82.
Dahabreh IJ, Terasawa T, Castaldi PJ et al. Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern med. 2011;154:37-49.
Santini D, Spoto C, Loupakis F et al. High concordance of BRAF status between primary colorectal tumours and related metastatic sites: implications for clinical practice. Ann Oncol 2012; 21:1565.
Mao C, Liao RY, Qiu LX et al. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep 2011;38(4):2219-23.
Maughan TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomized phase 3 MRC COIN trial. Lancet 2011;377(9783):2103-14.
NCCN Clinical Practice Guidelines in Oncology™. Colon cancer. Version 3.2014 Cancer Network, Inc. Available at nccn.org
NCCN Clinical Practice Guidelines in Oncology™. Melanoma. Version 3.2015Cancer Network, Inc. Available at nccn.org
Bokemeyer C., Cutsem E.V., Rougier P., Ciardiello F., Heeger S., Schlichting M., Celik I., Kohne C.-H. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials (2012) European Journal of Cancer, 48 (10) , pp. 1466-1475
Cushman-Vokoun AM. Stover DG et al. Clinical Utility of KRAS and BRAF Mutations in a Cohort of Patients With Colorectal Neoplasms Submitted for Microsatellite Instability Testing.(2013) Clinical Colorectal Cancer epub ahead of print.
Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer [trunc]. Arch Pathol Lab Med. 2013 Jun;137(6):828-860.
American College of Medical Genetics and Genomics, Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genetics in Med. 2013 July:15(7): 517-527.
Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to antiepidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27:2091–2096.
AHRQ Tech Assessment
Date Reason Action
August 2011 Annual review Policy renewed
August 2012 Annual review Policy renewed
May 2013 Interim review Policy revised
July 2013 Annual review Policy revised
May 2014 Annual review Policy revised
April 2015 Annual review Policy revised
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.