BlueCross and BlueShield of Montana Medical Policy/Codes
Epidermal Growth Factor Receptor (EGFR) Mutation Analysis for Patients with Non-Small Cell Lung Cancer (NSCLC)
Chapter: Medicine: Tests
Current Effective Date: July 18, 2013
Original Effective Date: March 18, 2012
Publish Date: July 18, 2013
Revised Dates: April 23, 2013
Description

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) frequently over-expressed and activated in non-small cell lung cancer (NSCLC). Mutations in 2 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.

The test is intended for use in patients with advanced NSCLC. Patients with either small deletions in exon 19 or a point mutation in exon 21 (L858R) of the tyrosine kinase domain of the epidermal growth factor gene are considered good candidates for treatment with erlotinib.

This policy summarizes the evidence for using EGFR mutations to decide which patients with advanced NSCLC should be considered for erlotinib therapy and which are better suited for alternative therapies.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Medically necessary

Blue Cross Blue Shield of Montana (BCBSMT) may consider analysis of two types of somatic mutation within the epidermal growth factor receptor (EGFR) gene—small deletions in exon 19 and a point mutation in exon 21 (L858R)—medically necessary to predict treatment response to erlotinib in patients with advanced non- squamous cell, non-small cell lung cancer (NSCLC).

Investigational

BCBSMT considers analysis of two types of somatic mutation within the EGFR gene—small deletions in exon 19 and a point mutation in exon 21 (L858R)—experimental, investigational and unproven for patients with squamous cell NSCLC. 

Analysis for other mutations within exons 18-24, or other applications related to NSCLC, is considered experimental, investigational and unproven.

Rationale
 
Treatment options for non-small cell lung cancer (NSCLC) depend on disease stage and include various combinations of surgery, radiation therapy, chemotherapy, and best supportive care. Unfortunately, in up to 85% of cases, the cancer has spread locally beyond the lungs at diagnosis, precluding surgical eradication. In addition, up to 40% of patients with NSCLC present with metastatic disease. (1) 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%. (2, 3)

Laboratory and animal experiments have shown that therapeutic interdiction of the epidermal growth factor receptor (EGFR) pathway could be used to halt tumor growth in solid tumors that express EGFR. (4) These observations led to the development of 2 main classes of anti-EGFR agents for use in various types of cancer: small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (MAbs) that block EGFR-ligand interaction. (5)

Two orally administered EGFR-selective small molecules (quinazolinamine derivatives) 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 U.S.

Two publications (6, 7) demonstrated that the underlying molecular mechanism underpinning dramatic responses in these favorably prognostic groups appeared to be the presence of activating somatic mutations in the TK domain of the EGFR gene, notably small deletions in exon 19 and a point mutation in exon 21 (L858R). These can be detected by direct sequencing or polymerase chain reaction (PCR) technologies.

A Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment on this topic was first published in November 2007. (8) The 2007 Assessment concluded that there was insufficient evidence to permit conclusions about the clinical validity or utility of EGFR mutation testing to predict erlotinib sensitivity or to guide treatment in patients with NSCLC. This Assessment has recently been revised, (9) with new conclusions indicating EGFR mutation testing has clinical utility in selecting or deselecting patients for treatment with erlotinib.

Thirteen publications have been published that provide data on EGFR mutations in tumor samples obtained from NSCLC patients in erlotinib treatment studies. Nine of these (10-18) were nonconcurrent-prospective studies of patients treated with erlotinib and then studied for the presence or absence of mutations, 4 (Table 1) were prospective 1-arm enrichment studies of mutation-positive (3 studies) (19-21) or wild-type (1 study) (22) 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 (Table 2). 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 between 0% and 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 (PFS) 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) (Table 2). In all cases in which these data were reported, EGFR-mutation-positive tumors showed a trend or a statistically significant increase in PFS rate

Overall survival (OS) 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) (Table 2). In all cases in which these data were reported, EGFR-mutation-positive tumors showed a trend or a statistically significant increase in survival rate.

In the 3 prospective studies of EGFR mutation-positive patients (Table 1), (19-21) objective radiologic response rates were 40% to 70%, PFS times were 8 to 14 months, and OS times were 16 to 29 months. This performance was distinctly different than that observed in wild-type patients (22) (Table 2) who exhibited an objective radiologic response of 3.3%, a PFS of 2.1 months, and an OS of 9.2 months.

Of note, EGFR mutations appear to provide prognostic, as well as predictive information about the behavior of tumors. In the study by Eberhard et al.,(15) 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 OS (not reached versus 10 months [p<0.001]).

In a pooled analysis of studies, EGFR mutations appear to demonstrate improved patient outcomes for patients treated with erlotinib, as compared to standard chemotherapy (median PFS of 13.2 versus 5.9 months, respectively). (23) Patients with EGFR mutations appear to be ideal candidates for treatment with 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.

Table 1. Clinical Response in Prospective Studies of Erlotinib Therapy in Patients with EGFR Gene Mutation-Positive Advanced NSCLC*

Study

(Yr) 

No. Mutated/No. Tested

(%)

Mutation Positive Objective Radiologic Response (%)

Median Progression-free Survival(mos.)

[95% CI]

Median Overall Survival (mos.)[95% CI]

Jackman et al. (2009) Prospective 1-arm treatment EGFR-positive patients with erlotinib, chemotherapy naïve (19) 

84 enrolled

 

70

 

13

 

28.7

 

Rosell et al. (2009) Prospective 1-arm treatment EGFR-positive patients with erlotinib in treatment failure and chemotherapy naïve (20) 

350/2105

(16.6)

 

70

 

14

[11.3-16.7]

 

27

[24.9-33.1]

 

Sun et al. (2010) Prospective 1-arm treatment EGFR-positive patients with erlotinib in treatment failures (21) 

144/164

(32)

 

40

 

8

 

15.8

 

Yoshioka et al. (2010) Prospective 1-arm treatment EGFR wild-type patients with erlotinib in treatment failures (22) 

30 enrolled

 

Mutation Negative

3.3

2.1

 

9.2

 

* all patients had stage IIIA/IV NSCLC

Abbreviation: CI, confidence interval

Table 2. Outcomes in Patients According to EGFR Mutation Status in Response to Treatment with Erlotinib (9 studies of 630 patients)

Endpoint

 

Overall Radiologic Response Rate – Median (range), %

Progression-Free Survival – Median (range), mos.

Overall Survival – Median (range), mos.

EGFR-Positive Patients  

45 (0 – 83) 

12.5 (6.8 – 13.1)  

21 (10 – 35) 

Wild-Type Patients  

5.5 (0 – 18) 

2.5 (1.4 – 5) 

8.1 (3 -12)

Untested Patients (Intent to Treat) – FDA Label 

 

2.8 

12

Rosell et al. (20) reported mutations in 16.6% of the total patients studied but noted these were found more frequently in women (69.7%), in patients who had never smoked (66.6%), and in patients with adenocarcinomas (80.9%). Based on these findings, Rosell et al. recommended EGFR-mutation screening in women with lung cancer with nonsquamous cell tumors who have never smoked. Other reports on the frequency of mutations have also revealed a higher prevalence in East Asians when compared to other ethnicities (38% versus 15%, respectively).(18) An increased incidence of mutations is clearly seen in these special populations (women, patients with adenocarcinoma, nonsmokers, and/or Asians); however, it does appear that a substantial number of patients without these selected demographics still exhibit EGFR mutations and would benefit from erlotinib treatment.

In a comprehensive analysis of 14 studies involving 2,880 patients, Mitsudomi et al. (24) noted mutations were observed in 10% of men, 7% of non-Asian patients, and 7% of current or former smokers, but only 2% of patients with nonadenocarcinoma histologies. While histology appears to be the strongest discriminating factor, results are diverse across studies. Eberhard et al.(15) observed mutations in 6.4% of patients with squamous cell carcinomas (SCCs) and Rosell et al.(20) in 11.5% of patients with large cell carcinomas. Numbers in these studies were small.

The National Comprehensive Cancer Network (NCCN) (25) has recently recommended testing not be performed in SCCs because of the low incidence identified in the Catalogue of Somatic Mutations in Cancer (COSMIC) maintained by the Sanger Institute. (26) This database of 1,873 samples of squamous cell lung cancers was noted to contain EGFR mutations in 2.7% of samples with an upper confidence interval (CI) for the true incidence of mutations reported to be 3.6% or less.

Park et al. (27) in a preselected set of Korean patients treated with gefitinib, reported EGFR mutations to be present in 3 out of 20 (15%) male smokers with SCC, a patient subgroup that based on demographics should have a low yield of EGFR mutations. Two of the 3 patients identified with the mutation exhibited a response to the drug versus a response in 1 of 17 wild-type patients. The PFS in patients with EGFR was 5.8 months, compared to 2.4 months in the wild-type group (not statistically significant, p=0.07, but suggesting a trend favoring a treatment response in patients with the mutation).

In vivo studies by Dobashi et al.(28) have recently been reported showing that in tumors in Japanese patients with both adenocarcinomas and SCCs, EGFR mutations are associated with downstream phosphorylation of EGFR and constitutive activation of the EGFR pathway.

Both of these studies appear to support the potential value of testing in patients with tumors of squamous cell histology, particularly in Asians. However, similar studies have not been reported in non-Asian populations or in populations treated with erlotinib.

Gene sequencing is generally considered an analytical gold standard. A rapid response report on EGFR-mutation analysis has recently been published by the Canadian Agency for Drugs and Technologies in Health. (29) Based on an analysis of 11 observational studies evaluating the use of PCR-based strategies to detect mutations in the EGFR gene, this report concluded PCR-based approaches are capable of identifying mutations in the EGFR gene with a sensitivity equivalent to that of direct sequencing.

In a Phase 3 prospective clinical trial in China, Zhou et al. (30) reported the results of first-line treatment of patients with EGFR-mutation positive NSCLC randomized to treatment with erlotinib (n=83) versus standard chemotherapy (gemcitabine plus carboplatin) [n=82]). They observed a significant increase in PFS compared to treatment with chemotherapy (13.1 vs. 4.5 months; hazard ratio [HR] 0.16 (p<0.0001). Patients treated with erlotinib experienced fewer grade 3 and 4 toxic effects than those on chemotherapy.

Petrelli et al. (31) reported a meta-analysis of 13 randomized trials of 1,260 patients receiving tyrosine kinase inhibitors for first-line, second-line or maintenance therapy and compared outcomes to standard therapy. Overall, they noted that in patients with EGFR mutations, use of EGFR TKIs increased the chance of obtaining an objective response almost 2-fold when compared to chemotherapy. Response rates were 70% vs. 33% in first-line trials and 47% versus 28.5% in second-line trials. Tyrosine kinase inhibitors reduced the hazard of progression by 70% in all trials and by 65% in first-line trials; however, overall they did not improve survival.

Summary

Non-concurrent prospective studies, single-arm enrichment studies, and one small randomized study demonstrate that the detection of EGFR gene mutations identifies patients who are likely to benefit from use of erlotinib and who therefore represent ideal candidates for treatment with this drug. 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.

Patients who are found to have wild-type tumors are unlikely to respond to erlotinib. They should be considered candidates for alternative therapies.

EGFR mutational analysis may be considered medically necessary to predict treatment response to erlotinib in patients with advanced NSCLC; however, EGFR mutational analysis is experimental, investigational and unproven in patients with NSCLC of squamous-cell type.

National Comprehensive Cancer Network (NCCN) Guidelines

The National Comprehensive Cancer Network (NCCN) in the V2.2012 guidelines on non-small-cell lung cancer (25) recommends EGFR mutational analysis in patients with advanced NSCLC. It does suggest testing be deferred in patients with squamous cell carcinomas because of the low incidence of mutation in this histopathology type.

ASCO Publication Recommendations

In a 2011 publication, (32) the American Society of Clinical Oncology (ASCO) issued a provisional clinical opinion on EGFR mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. It concludes patients with NSCLC being considered for first-line therapy with an EGFR tyrosine kinase inhibitor should have their tumor tested for EGFR mutations to determine whether an EGFR tyrosine kinase inhibitor or chemotherapy is the appropriate first-line therapy.

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

Rationale for Benefit Administration

ICD-9 Codes

162.3-162.9

ICD-10 Codes
C34.0-C34.92
Procedural Codes: 83890, 83891, 83892, 83893, 83894, 83895, 83896, 83897, 83898, 83899, 83810, 83811, 83812, 84999
References
  1. Fathi AT, Brahmer JR. Chemotherapy for advanced stage non-small cell lung cancer. Semin Thorac Cardiovasc Surg 2008; 20(3):210-6.
  2. Martoni A, Marino A, Sperandi F et al. Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer 2005; 41(1):81-92.
  3. Rudd RM, Gower NH, Spiro SG et al. Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. J Clin Oncol 2005; 23(1):142-53.
  4. Fruehauf J. EGFR function and detection in cancer therapy. J Exp Ther Oncol 2006; 5(3):231-46.
  5. Heymach JV. ZD6474--clinical experience to date. Br J Cancer 2005; 92 Suppl 1:S14-20.
  6. 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; 350(21):2129-39.
  7. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304(5676):1497-500.
  8. Epidermal growth factor receptor (EGFR) mutations and tyrosine kinase inhibitor therapy in advanced non-small-cell lung cancer.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program. (2007 November)  22 (6) : 1-22.  
  9. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Epidermal growth factor receptor (EGFR) mutations and tyrosine kinase inhibitor therapy in advanced non-small-cell lung cancer. TEC Assessments 2011.
  10. 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; 14(12):3860-6.
  11. 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; 5(2):169-78.
  12. Felip E, Rojo F, Reck M et al. A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. Clin Cancer Res 2008; 14(12):3867-74.
  13. 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; 26(9):1472-8.
  14. Schneider CP, Heigener D, Schott-von-Romer K et al. Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study. J Thorac Oncol 2008; 3(12):1446-53.
  15. 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.
  16. Giaccone G, Gallegos Ruiz M, Le Chevalier T et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res 2006; 12(20 Pt 1):6049-55.
  17. Jackman DM, Yeap BY, Lindeman NI et al. Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol 2007; 25(7):760-6.
  18. Zhu CQ, da Cunha Santos G, Ding K et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008; 26(26):4268-75.
  19. 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; 15(16):5267-73.
  20. Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361(10):958-67.
  21. Sun JM, Won YW, Kim ST et al. The different efficacy of gefitinib or erlotinib according to epidermal growth factor receptor exon 19 and exon 21 mutations in Korean non-small cell lung cancer patients. J Cancer Res Clin Oncol 2010.
  22. Yoshioka H, Hotta K, Kiura K et al. A phase II trial of erlotinib monotherapy in pretreated patients with advanced non-small cell lung cancer who do not possess active EGFR mutations: Okayama Lung Cancer Study Group trial 0705. J Thorac Oncol 2010; 5(1):99-104.
  23. Paz-Ares L, Soulieres D, Melezinek I et al. Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: pooled analysis. J Cell Mol Med 2010; 14(1-2):51-69.
  24. Mitsudomi T, Kosaka T, Yatabe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol 2006; 11(3):190-8.
  25. National Comprehensive Cancer Network (NCCN). NCCN Guidelines: Non-small cell lung cancer. 2011. Version 2.2012. Available oneline at www.nccn.org . Last accessed December 2, 2011.
  26. Forbes SA, Bhamra G, Bamford S et al. The Catalogue of Somatic Mutations in Cancer (COSMIC). Current protocols in human genetics / editorial board, Jonathan L Haines [et al] 2008; Chapter 10:Unit 10 11.
  27. Park SH, Ha SY, Lee JI et al. Epidermal growth factor receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung. Journal of Korean medical science 2009; 24(3):448-52.
  28. Dobashi Y, Suzuki S, Kimura M et al. Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human lung carcinomas. Human pathology 2011; 42(2):214-26.
  29. Mujoomdar ML, Mouton K, Spry C. Epidermal growth factor receptor mutation analysis in Advanced non-small cell lung cancer: a review of the clinical effectiveness and guidelines. . Canadian Agency for Drugs and Technologies in Health 2010.
  30. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The lancet oncology 2011; 12(8):735-42.
  31. 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. Clinical lung cancer 2011.
  32. 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.
  33. Epidermal Growth Factor Receptor (EGFR) Mutation Analysis for Patients with Non-Small Cell Lung Cancer (NSCLC). Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 January) Medicine 2.04.45.
History
January 2012 New Policy: no specific CPT codes to edit.
April 2013 Policy formatting and language revised.  Policy statement unchanged.  Removed non-specific codes 83890, 83891, 83892, 83893, 83894, 83895, 83896, 83897, 83898, 83899, 83810, 83811, 83812, 84999.  Added code 81235.
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Epidermal Growth Factor Receptor (EGFR) Mutation Analysis for Patients with Non-Small Cell Lung Cancer (NSCLC)