Notification



Notification Issue Date:



Policy Attachment

Attachment to Policy # MA06.008b


Attachment:E

Policy #:MA06.008b

Description:KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer Prior to Use of Cetuximab (Erbitux®) and Pantiumumab (Vectibix®)

Title:Pharmacogenetic Testing to Determine Drug Sensitivity

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.


Title: KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer Prior to Use of Cetuximab (Erbitux®) and Pantiumumab (Vectibix®)

POLICY

Coverage is subject to the terms, conditions, and limitations of the member's Evidence of Coverage.

MEDICALLY NECESSARY

KRAS mutation analysis may be considered medically necessary to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) in the treatment of metastatic colorectal cancer.

EXPERIMENTAL/INVESTIGATIONAL

BRAF mutation analysis is considered experimental/investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) in the treatment of metastatic colorectal cancer.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

POLICY GUIDELINES

There is no Medicare coverage determination addressing this service; therefore, the Company policy is applicable.

BENEFIT APPLICATION

KRAS
Subject to the terms and conditions of the applicable Evidence of Coverage, KRAS mutation analysis to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) in the treatment of colorectal cancer is covered under the medical benefits of the Company's Medicare Advantage products when the medical necessity criteria in this medical policy are met.

BRAF
Subject to the terms and conditions of the applicable Evidence of Coverage, BRAF mutation analysis predict nonresponse to anti-EGFR monoclonal antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) in the treatment of metastatic colorectal cancer is not eligible for payment under the medical benefits of the Company's Medicare Advantage products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are excluded from the Company's Medicare Advantage products. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION STATUS

Genetic testing is a laboratory procedure and is historically not regulated by the US Food and Drug Administration (FDA). Clinical Laboratory Improvement Amendments (CLIA) establishes quality standards for all laboratory testing. However, recently, the FDA is reported to be involved in the evaluation of the service of genetic testing.

DESCRIPTION

METASTATIC COLORECTAL CANCER (CRC) AND KRAS
Cetuximab (Erbitux®, ImClone Systems) and panitumumab (Vectibix®, Amgen) are approved in the treatment of colorectal cancer (CRC) in refractory disease, and ongoing studies are investigating the use of these epidermal growth factor receptor (EGFR) inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy. Some individuals with CRC have tumors with a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation that may affect tumor response to (EGFR) inhibitors.

KRAS mutation analysis, which uses polymerase chain reaction (PCR) methodology is commercially available as a laboratory-developed test. Tests such as this are regulated under the Clinical Laboratory Improvement Amendments (CLIA). FDA Premarket approval is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing.

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. Data supports the use of KRAS mutation analysis prior to any use of cetuximab or panitumumab in a treatment regimen. The ability to identify individuals whose tumors express mutated KRAS will prevent unnecessary exposure of these individuals to products that are not helpful or effective and also protect them from drug toxicity. Additionally, identification of individuals who will not benefit from cetuximab (Erbitux®) or panitumumab (Vectibix®) will allow providers to discuss alternative treatment plans with their patients.

METASTATIC COLORECTAL CANCER (CRC) AND BRAF
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. Studies have indicated a shorter survival and lack of response to cetuximab or panitumumab in metastatic colorectal cancer patients. However, study designs had several limitations and included a small number of patients. Larger studies are required to confirm these findings. Furthermore, validity of commercially available assays for the BRAF p.Val600Glu sequence variants is not well established. Presently there is not enough evidence to determine the clinical utility of BRAF V600E mutation testing in patients with colon and colorectal cancers.

REFERENCES

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.

Barault L, Charon-Barra C, Jooste V, et al. Hypermethylator phenotype in sporadic colon cancer: Study on a population-based series of 582 cases. Cancer Res. 2008;68(20):8541-8546.

Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67(6):2643-2648.

Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). KRAS mutations and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer. TEC Assessments 2008; Volume 23, Tab 6.

Bokemeyer C , Bondarenko I , Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27(5):663-71.

Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer. 2008;99(1):83-9.

Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007;96(8):1166-9.

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;19(3):508-15.

De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753-62.

Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705–12.

Freeman DJ, Juan T, Reiner M, et al. Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin Colorectal Cancer. 2008;7(3):184–90.

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;359(17):1757-65.

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

Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27(35):5924–5930.

Lea A, Allingham-Hawkins D, Levine S. BRAF p.Val600Glu (V600E) testing for assessment of treatment options in metastatic colorectal cancer. PLoS Curr. 2010;2:RRN1187.

Lievre A, Blons H, Laurent-Puig P. Oncogenic mutations as predictive factors in colorectal cancer. Oncogene. 2010;29(21):3033-3043.

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):374-379.

Lin JS, Webber EM, Senger CA, Holmes RS, Whitlock EP. Systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic colorectal cancer. Am J Cancer Res. 2011;1(5):650-662.

Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009;101(4):715-721.

Mao C, Liao RY, Qiu LX, Wang XW, Ding H, Chen Q. 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):2219-2223.

Molinari F, Martin V, Saletti P, et al. Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br J Cancer. 2009;100(7):1087-94.

Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: A cohort study. Lancet Oncol. 2005;6(5):279-286.
Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005;6(5):279-86.

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Colon cancer. Version 1.2011. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed July 31, 2013.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology, Colon Cancer (version 2.2012). 2011:1-101.

Perrone F, Lampis A, Orsenigo M, et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol. 2009;20(1):84-90.

Phillips B, Kalady M, Kim R. BRAF testing in advanced colorectal cancer: is it ready for prime time? Clin Adv Hematol Oncol. 2010;8(6):437-44.

Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One. 2009;4(10):e7287.

Souglakos J, Philips J, Wang R, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009;101(3):465-472.

Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563-72.

Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98-9.

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.

Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408-17.

Van Cutsem 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. Paper presented at: American Society of Clinical Oncology 2010 Gastrointestinal Cancers Symposium (GCS); January 22-24, 2010; Orlando, FL.

Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011-2019.


Coding Table
Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

Code System
Code Number and Code Narrative
CPT KRAS
81275, 81403, 88363
BRAF
81210
ICD-10 Diagnosis N/A
ICD-10 Procedure N/A
HCPCS G0452 Molecular pathology procedure; physician interpretation and report


Version Effective Date: 07/01/2016
Version Issued Date: 07/01/2016
Version Reissued Date: 10/10/2019

Connect with Us        


© 2017 Independence Blue Cross.
Independence Blue Cross is an independent licensee of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.