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Medical Policy: 02.04.31
Original Effective Date: February 2011
Reviewed: February 2012
Revised:
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:
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) frequently overexpressed and activated in non-small cell lung cancer (NSCLC). Mutations in two regions of the EGFR gene (exons 18-24)—small deletions in exon 19 and a point mutation in exon 21 (L858R)—appear to predict tumor response to tyrosine kinase inhibitors (TKIs) such as erlotinib.
Treatment options for NSCLC depend on disease stage and include various combinations of surgery, radiation therapy, chemotherapy and best supportive care. In up to 85% of cases the cancer has spread locally beyond the lungs at diagnosis, precluding surgical eradication. Additionally, up to 40% of patients with NSCLC present with metastatic disease. When treated with standard platinum-based chemotherapy, patients with advanced NSCLC have a median survival of 8 to 11 months and a 1-year survival of 30 to 45%. Studies have shown that therapeutic interdiction of the EGFR pathway could be used to halt tumor growth in solid tumors that express EGFR.
Two orally administered EGFR-selective small molecules have been identified for use in treating NSCLC: gefitinib (Iressa®, AstraZeneca) and erlotinib (Tarceva®, Genentech BioOncology). While both are available for use in Europe, Canada, and Asia, only erlotinib is available for use in new patients in the United States.
Thirteen peer-reviewed publications have provided data on EGFR mutations in tumor samples obtained from NSCLC patients in erlotinib treatment studies. Nine of these were
non-concurrent-prospective studies of patients treated with erlotinib and then studied for the presence or absence of mutations. Four were prospective one-arm enrichment studies of mutation-positive (3 studies) or wild-type (1 study) patients treated with erlotinib.
Data comparing erlotinib results in EGFR mutation-positive versus wild-type patients have been reported in 9 studies of 630 patients. In studies of treatment with erlotinib, objective radiologic response rates in patients with EGFR-mutation-positive tumors ranged from 0 to 83% (median 45%) compared to objective radiologic response rates in patients with wild-type tumors of from 0 to 18% (median 5.5%). In the 5 studies statistically evaluating results, patients with EGFR-mutation-positive tumors always demonstrated statistically significant increases in objective radiologic response.
Progression-free survival in patients with EGFR-mutation-positive tumors ranged from 6.8 to 13.1 months (median 12.5) and in wild type tumors ranged from 1.4 to 5 months (median 2.5). In all cases where these data were reported, EGFR-mutation-positive tumors showed a trend or a statistically significant increase in progression-free survival rate. Overall survival in patients with EGFR-mutation-positive tumors ranged from 10 to 35 months (median 21) and in wild type tumors ranged from 3 to 12 months (median 8.1). In all cases where these data were reported, EGFR-mutation-positive tumors showed a trend or a statistically significant increase in survival rate.
In the three prospective studies of EGFR mutation-positive patients, objective radiologic response rates were 40 to 70%, progression-free survival times were 8 to 14 months, and overall survival times were 16 to 29 months. This performance was distinctly different than that observed in wild type patients who exhibited an objective radiologic response of 3.3%, a progression-free survival of 2.1 months and an overall survival of 9.2 months.
Of note, EGFR mutations appear to provide prognostic as well as predictive information about the behavior of tumors. In a study by Eberhard et al., improved outcome parameters were observed in EGFR positive patients compared to wild type patients for the population as a whole (standard chemotherapy and standard chemotherapy with erlotinib) in all measurement categories, with objective radiologic response of 38% versus 23% (p=0.01), time to progression of 8 months versus 5 months (p<0.001) and overall survival (not reached versus 10 months [p<.001]).
EGFR mutations appear to demonstrate improved patient outcomes for patients treated with erlotinib as compared to standard chemotherapy (median progression free survival of 13.2 versus 5.9 months). Patients with EGFR mutations appear to be ideal candidates for treatment with erlotinib whereas wild type patients appear to derive little detectable benefit from erlotinib. Identification of patients likely to respond or to fail to respond to erlotinib treatment leads to tailored choices of treatment likely to result in predictable and desirable outcomes. These observations have been made in a population composed primarily of tumors with adenocarcinoma histology. There is currently no evidence to indicate whether this behavior is also seen in patients with squamous cell histology.
Two additional studies published in 2011 continue to demonstrate the clinical utility of EGFR mutation analysis in the determination of whether an EGRF TKI (i.e., erlotinib) or chemotherapy is the appropriate first-line therapy.
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Prior Approval:
Not applicable
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Policy:
Epidermal Growth Factor Receptor (EGFR) mutation testing may be considered medically necessary in patients with advanced non-small cell lung cancer (NSCLC) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor (TKI).
Epidermal Growth Factor Receptor (EGFR) mutation testing is considered investigational for patients with advanced NSCLC of squamous cell-type.
Analysis for other mutations within exons 18-24, or other applications related to NSCLC, is considered investigational.
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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.
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Selected References:
- Eberhard DA, Johnson BE, Amler LC et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005; 23(25):5900-9.
- Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. Epub 2004 Apr 29.
- Jackman DM, Miller VA, Cioffredi LA et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009 Aug 15;15(16):5267-73. Epub 2009 Aug 11.
- Paz-Ares L, Soulietes D, Melezinek I et al. Clinical outcomes in non-small cell lung cancer patients with EGFR mutations: pooled analysis. J Cell Mol Med. 2010 Jan;14(1-2):51-69. Epub 2009 Dec 8.
- Mitsudomi T, Kosaka T, Yatabe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol. 2006 Jun;11(3):190-8.
- Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009 Sep 3;361(10):958-67. Epub 2009 Aug 19.
- Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004 Jun 4;304(5676):1497-500. Epub 2004 Apr 29.
- Ahn MJ, Park BB, Ahn JS et al. Are there any ethnic differences in molecular predictors of erlotinib efficacy in advanced non-small cell lung cancer? Clin Cancer Res. 2008 Jun 15;14(12):3860-6.
- Amann JM, Lee JW, Roder H et al. Genetic and proteomic features associated with survival after treatment with erlotinib in first-line therapy of non-small cell lung cancer in Eastern Cooperative Oncology Group 3503. J Thorac Oncol. 2010 Feb;5(2):169-78.
- Miller VA, Riely GJ, Zakowski MF et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 2008 Mar 20;26(9):1472-8.
- Azzoli CG, Baker S Jr, Temin S et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small cell lung cancer. J Clin Oncol. 2009 Dec 20;27(36):6251—66. Epub 2009 Nov 16.
- Blue Cross Blue Shield Association Technology Evaluation Center (TEC). (2010). Epidermal Growth Factor Receptor Mutation and Tyrosine Kinase Inhibitor Therapy in Advanced Non-small Cell Lung Cancer. TEC Assessments, (draft); 2010.
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Mujoomdar M, Moulton K, Spry C. Epidermal Growth Factor Receptor Mutation Analysis in Advanced Non-small Cell Lung Cancer: A Review of the Clinical Effectiveness and Guidelines. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2010. Available online at: http://www.cadth.ca/media/pdf/M0017_EGFR_Testing_for_NSCLC_e.pdf.
Last accessed December 2010.
- Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug; 12(8):735-42. Epub 2011 Jul 23.
- Petrelli F, Borgonovo K, Cabiddu M et al. Efficacy of EGFR Tyrosine Kinase Inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer. 2011 Nov 5. [Epub ahead of print].
- Ludovini V, Bianconi F, Pistola L et al. Optimization of patient selection for EGFR-TKIs in advanced non-small cell lung cancer by combined analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations. Cancer Chemother Pharmacol. 2012 Feb 1. [Epub ahead of print].
- Brugger W, Thomas M. EGFR-TKI resistant non-small-cell lung cancer (NSCLC): New developments and implications for future treatment. Lung Cancer. 2012 Jan 24. [Epub ahead of print].
- Keedy VL, Temin S, Somerfield MR et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol 2011; 29(15):2121-7.
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Policy History:
Date Reason Action
February 2011 Literature review New policy
February 2012 Annual review Policy renewed
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.
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