BlueCross and BlueShield of Montana Medical Policy/Codes
KRAS Mutation Analysis in Non-Small-Cell Lung Cancer
Chapter: Medicine: Tests
Current Effective Date: December 27, 2013
Original Effective Date: February 26, 2009
Publish Date: December 27, 2013
Revised Dates: March 1, 2010; June 1, 2011; March 21, 2012; December 11, 2013

The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene can harbor mutations that may interfere with the activity and effectiveness of certain drugs used to treat specific cancers. KRAS mutations are found in approximately 15-30% of lung cancer tumors. KRAS mutation analysis is commercially available as a laboratory developed test.

KRAS mutation analysis is commercially available from Genzyme Genetics and Medical Solutions™. These tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Pre-market approval from the United States Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing.

KRAS Mutation Analysis in Non-Small Cell Lung Cancer (NSCLC)

Erlotinib (Tarceva®) received approval from the FDA in November 2004 as salvage therapy for advanced NSCLC, based on results of a phase III clinical trial that demonstrated a modest survival benefit: 6.7 months median survival compared to 4.7 months in the placebo group. The FDA approved Gefitinib (Iressa®) in 2003 through the agency’s accelerated approval process, based on the initially promising results of phase II trials. The labeled indication was limited to patients with NSCLC who had failed two or more prior chemotherapy regimens. However, in December 2004, results of phase III trials became available, suggesting that gefitinib was not associated with a survival benefit. In May 2005, the FDA revised the labeling of gefitinib to limit its use to patients who were currently benefiting from the drug, or who had benefited in the past, and that no new patients were to be given the drug.

Although gefitinib fell out of use in the United States in 2005, it continued to be used elsewhere in the world, and a recent study was published (“Iressa in NSCLC Trial Evaluating Response and Survival vs Taxotere,” or “INTEREST” trial) that involved 1,466 patients from 24 countries outside of the United States. All of the patients had advanced or metastatic disease and had been previously treated with at least one platinum-containing regimen, and were randomized to receive either gefitinib or docetaxel. Of the 1,466 patients, 1433 were evaluable. Objective tumor response rates and progression-free and overall survival were similar for the two groups; however, gefitinib was associated with lower rates of treatment related adverse events than docetaxel. The authors state that based on their findings, they are hopeful that gefitinib can return as a treatment for lung cancer in the United States.

Gefitinib is currently in very limited use in the U.S., and only as part of a special access program.


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Analysis of mutations of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) may be considered medically necessary as a predictor of non-response to tyrosine kinase inhibitor (e.g., Erlotinib [Tarceva®]) in non-small-cell lung carcinoma (NSCLC).

KRAS mutation analysis is considered experimental, investigational and unproven for all other non-small-cell lung carcinoma indications.


Data on the role of KRAS mutations in non-small-cell lung cancer (NSCLC) and response to erlotinib are available from two Phase III trials, which conducted non-concurrent subgroup analyses of the efficacy of TKIs in patients with wild-type (non mutated) versus mutated KRAS lung tumors, three phase II trials and one retrospective single-arm study. The data from these studies suggest that KRAS mutations may be useful to predict non-response to TKIs in NSCLC.

Pao et al. were the first to suggest that patients with KRAS mutated lung tumors were non-responsive to treatment with EGFR TKIs. (1) Thirty-six patients with bronchioloalveolar carcinoma underwent KRAS mutation analysis; nine were found to harbor KRAS mutations. Response was measured by a single radiologist, who graded responses according to Response Evaluation Criteria in Solid Tumors (RECIST), blinded to patient outcome. Zero of the nine patients with KRAS-mutated tumors responded to erlotinib (p=0.5531).

Zhu et al. performed a non-concurrent subgroup analysis of KRAS mutations in a group of patients with advanced NSCLC who had failed standard chemotherapy treatment and had been previously randomized to receive erlotinib or placebo. (9) The original Phase III trial (National Cancer Institute of Canada Clinical Trials Group Study BR.21) was the first to demonstrate a significant survival advantage with the use of an EGFR TKI in previously treated NSCLC patients. (2) In the subsequent analysis, 206 of the original 731 tumors were tested for KRAS mutations, which were identified in 30 (15%) patients. Among the 206 patients tested for KRAS mutations, 118 were assessable for response to erlotinib. Of the 98 patients with wild-type KRAS, 10 (10.2%) responded to erlotinib, whereas of the 20 with mutated KRAS, only one (5.0%) patient responded [hazard ratio (erlotinib versus placebo) 1.67 (95% CI (confidence interval): 0.62–4.50; p=0.31) in patients with KRAS mutations and 0.69 (95% CI: 0.49–0.97; p=0.03) in wild-type patients]. In the Cox regression model, the interaction between KRAS mutation status and treatment was p=0.09.

Eberhard et al. performed a non-concurrent subgroup analysis of KRAS mutations in a group of previously untreated patients with advanced NSCLC who had been randomized to receive chemotherapy with or without erlotinib.(3) The original Phase III trial (TRIBUTE study) randomized patients to carboplatin and paclitaxel either with erlotinib or with placebo. (4) Of the original 1,079 patients, tumor DNA from 274 patients was sequenced for KRAS mutations. The baseline demographics between patients with available tumor DNA and those without were balanced. KRAS mutations were detected in 55 of the 274 (21%). The response rate for patients with wild-type KRAS tumors was 26%, regardless of which therapy they received. In patients with KRAS-mutated tumors, response rate was 8% for those receiving erlotinib with chemotherapy, versus 23% in the group receiving chemotherapy alone (p=0.16; 95% CI for difference -5% to 35%). Patients with mutated KRAS who received erlotinib had shortened overall survival of 4.4 months (95% CI: 3.4–12.9 months) versus 13.5 months (95% CI: 11.1–15.9 months) in those who received chemotherapy alone (p=0.019).

In a Phase II, multicenter, open-label study, Jackman et al. evaluated the treatment response to erlotinib in chemotherapy-naive patients 70 years of age or older and who had advanced NSCLC. (6) Of the 80 patients eligible for treatment, 41 had tumor analysis for KRAS mutations. Six of the 41 (15%) had KRAS mutations detected. None of the six patients with a KRAS mutation responded to erlotinib, whereas five of 35 (14%) patients with wild-type KRAS had a partial response.

In a Phase II trial, Miller et al. compared response to erlotinib in 101 patients with lung bronchioloalveolar carcinoma (n=12) or adenocarcinoma, bronchioloalveolar subtype (n=89) according to KRAS mutational status. (8) Of the patients with evaluable tumor, 18 patients (18%) had KRAS-mutated tumors, and none of them responded to erlotinib (zero of 18; 95% CI: 0% to 19%; p<0.01). Response rate was 32% in patients without a KRAS mutation. Median overall survival in patients with a KRAS-mutated tumor was 13 months versus 21 months in patients with KRAS wild-type tumors (p=0.30).

In a Phase II trial, Giaccone et al. studied response to erlotinib in 53 chemotherapy-naive patients with advanced NSCLC. (5) Histologic material was available to assess KRAS mutational status from 29 patients, 10 of whom had mutations. All 10 were non-responders to erlotinib (p=0.125).

2009 National Cancer Institute Clinical Trials Database (PDQ®) and

Two Phase III trials are currently ongoing to assess erlotinib in NSCLC patients with concurrent analysis of KRAS mutations. One phase III trial will assess whether clinical and biological features are able to predict the efficacy of erlotinib in patients with NSCLC as second and subsequent line therapy (Tarceva Italian Lung Optimization Trial [TAILOR]; NCT00637910). Outcome measures are overall survival, progression free survival and tumor response. Only patients with available tumor tissue will be included, and patients must have an absence of EGFR mutations. KRAS mutation analysis will be performed to determine the value of identifying a KRAS mutation using this type of therapy. Estimated enrollment is 1,500, and study completion date is estimated to be May 2012.

Another Phase III trial will assess the efficacy of pemetrexed versus erlotinib as second-line therapy in patients with advanced NSCLC (Marker Validation of Erlotinib in Lung Cancer [MARVEL]; NCT00738881). Outcome measures are progression-free survival, overall survival and response rate, with analysis of EGFR and KRAS mutations. Estimated enrollment is 957, and study completion date is estimated to be May 2011.

National Comprehensive Cancer Network (NCCN) 2009 Guidelines

NCCN guidelines state that patients with NSCLC whose tumors harbor KRAS mutations should consider first line therapy other than erlotinib (Tarceva).

2013 Update

A search of peer reviewed literature through May 2013 was performed. The following is a summary of the key literature to date.

Boldrini and colleagues reported on the association between the status of KRAS and EGFR mutations and several clinical variables in 411 patients with lung adenocarcinoma, as well as a subset analysis of tumor response in patients treated with one of the TKIs (erlotinib or gefitinib). (15) Overall, KRAS mutations were observed in 17.9% of patients. The subset analysis consisted of 21 female patients with stage IV disease who received a TKI as second- or third-line therapy and were assessed for radiographic tumor response using the Response Evaluation Criteria for Solid Tumors (RECIST). Age of this subpopulation at the time of diagnosis ranged from 40–86 years (mean age 60.8 years). Nineteen of the 21 patients were KRAS wild-type, and of those, 8 showed partial response, 4 had stable disease, and 7 had progressive disease. The 2 patients with KRAS mutations had progressive disease.

Schneider and colleagues reported on the relationship between clinical benefits and putative tumor markers in a subset of patients participating in a global open-label single-arm study (the TRUST study) of erlotinib in advanced NSCLC, involving 7,043 patients in 52 countries. (16) The subset of patients in this publication were all from German centers and consisted of 311 patients with stage IIIB/IV disease treated with erlotinib because they had failed or were not medically suitable for standard first-line chemotherapy. Tumor response was assessed using RECIST. Seventeen patients (15%) had KRAS mutations, and none of them had a response to erlotinib, but 2 had stable disease. The impact of KRAS mutation status on progression-free survival (PFS) and OS was of borderline statistical significance.

Campos-Parra and colleagues evaluated the response and progression-free survival (PFS) in platinum-based chemotherapy (CT) versus EGFR-TKIs in the presence or absence of KRAS mutation. Three hundred fifty three patients with NSCLC were treated with first-line CT, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were used in the second or third line of treatment. Clinical characteristics, mutation profile, response and PFS to CT and EGFR-TKIs, and overall survival were analyzed. The authors note in their results presence of the wild-type (WT) KRAS was independently associated with increased response rate to first-line CT when compared with KRAS mutation (41.4% vs. 14.7%; P=0.001). Conclusions reported from the authors indicated that KRAS mutation status is a good biomarker for response to EGFR-TKIs in patients with NSCLC. (17)


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ICD-9 Codes


ICD-10 Codes
Procedural Codes: 81275, 81403, 88363, 88381
  1. Pao, W., Wang, T.Y., et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Medicine (2005) 2(1):57-61.
  2. Shepherd, F.A., Rodrigues Pereira, J., et al. Erlotinib in previously treated non-small-cell lung cancer. New England Journal of Medicine (2005) 353(2):123-32.
  3. Eberhard, D.A., Johnson, B.E., 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. Journal of Clinical Oncology (2005) 23(25):5900-9.
  4. Herbst, R.S., Prager, D., et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. Journal of Clinical Oncology (2005) 23(25):5892-9.
  5. Giaccone, G., Gallegos Ruiz, M., et al. Erlotinib for front-line treatment of advanced non-small cell lung cancer: a phase II study. Clinical Cancer Research (2006) 12(20):6049-55.
  6. Jackman, D.M., Yeap, B.Y., 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. Journal of Clinical Oncology (2007) 25(7):760-6.
  7. Toschi, L., Cappuzzo, F. Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors. Oncologist (2007) 12(2):211-20.
  8. Miller, V.A., Riely, G.J., et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. Journal of Clinical Oncology (2008) 26(9):1472-8.
  9. Zhu, C.Q., da Cunha Santos, G., 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. Journal of Clinical Oncology (2008) 26(26):4268-75.
  10. Kim, E.S., Hirsh, V., et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet (2008) 372(9652):1809-18.
  11. KRAS Mutation Analysis in Non-small Cell Lung Cancer (NSCLC). Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2009 January) Medicine 2.04.55.
  12. Non-small Cell Lung Cancer. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.v.2.2009. Accessible at .          (accessed – 2009 September).
  13. NCCN Drugs and Compendium. National Comprehensive Cancer Network. Accessible at . (accessed – 2009 September).
  14. KRAS Mutation Analysis in Non-small-Cell Lung Cancer (NSCLC). Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2013 February) Medicine 2.04.55.
  15. Boldrini L, Ali G, Gisfredi S et al. Epidermal growth factor receptor and K-RAS mutations in 411 lung adenocarcinoma: a population-based prospective study. Oncol Rep 2009; 22(4):683-91.
  16. 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.
  17. Campos-Parra AD, Zuloaga C et al. KRAS Mutation as the Biomarker of Response to Chemotherapy and EGFR-TKIs in Patients With Advanced Non-Small Cell Lung Cancer: Clues For Its Potential Use in Second-Line Therapy Decision Making. Am J Clin Oncol. 2013 Mar 28.
June 2011 Updated policy statement to investigational, description, and references  
March 2012 Policy updated with literature search; no change to policy statement. No references added
December 2013 Policy formatting and language revised.  Policy statement previously investigational and revised to include: "Analysis of mutations of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) may be considered medically necessary as a predictor of non-response to tyrosine kinase inhibitor (e.g., Erlotinib [Tarceva®]) in non-small-cell lung carcinoma (NSCLC)".
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KRAS Mutation Analysis in Non-Small-Cell Lung Cancer