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Medical Policy: 02.04.20
Original Effective Date: October 2008
Reviewed: August 2011
Revised: April 2010
Benefit Application
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.
Description:
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 3 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. Five single-arm studies that have retrospectively analyzed KRAS mutation status and tumor response rate in patients with mCRC have shown a consistent lack of response to cetuximab or panitumumab in patients with KRAS mutation. Two of the 5 studies have also demonstrated progression-free and overall survival benefit with the use of EGFR inhibitors is limited to patients with wild-type KRAS. On-going studies are investigating the use of these EGFR inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy.
KRAS mutation analysis using polymerase-chain reaction (PCR) methods is commercially available as a laboratory-developed test in CLIA-licensed laboratories.
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Prior Approval:
Not applicable
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Policy:
KRAS mutation analysis is required prior to treatment of EGFR-expressing metastatic colorectal cancer with cetuximab and panitumumab to predict nonresponse and thereby establish medical necessity of cetuximab and panitumumab.
As a means of potentially further identifying likely responders to treatment with cetuximab or panitumumab, BRAF mutation analysis may be considered medically necessary ONLY in patients testing positive for wild-type KRAS.
See related medical policies:
05.01.19; Cetuximab
05.01.15; Panitumumab
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Procedure Codes and Billing Guidelines:
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To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
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S3713 KRAS mutation analysis testing
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Selected References:
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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.
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Van Cutsem E, Lang I, D’haens G et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 2008; 26(15 suppl):abstract 2.
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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].
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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.
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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.
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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.
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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.
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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].
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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.
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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.
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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.
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Van Custem E, Lang I, Folprecht G et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): The influence of KRAS and BRAF biomarkers on outcome: Updated data from the CRYSTAL trial. ASCO Gastrointestinal Cancer Symposium 2010; abstract 281.
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National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Colon Cancer. v.2.2010. Available at: www.nccn.org
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Policy History:
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Wellmark medical policies address the complex issue
of technology assessment of new and emerging treatments, devices,
drugs, etc. They are developed to
assist in administering plan benefits and constitute neither offers of
coverage nor medical advice. Wellmark medical policies contain only a
partial, general description of plan or program benefits and do not
constitute a contract. Wellmark does not provide health care services
and, therefore, cannot guarantee any results or outcomes.
Participating providers are independent contractors in private
practice and are neither employees nor agents of Wellmark or its
affiliates. Treating providers are solely responsible for medical
advice and treatment of members. Our medical policies may be updated
and therefore are subject to change without notice.
*Current Procedural Terminology © 2010 American Medical Association. All Rights Reserved.
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