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MP 2.04.55 KRAS Mutation Analysis in Non-Small Cell Lung Cancer (NSCLC)

Medical Policy    
Section
Medicine
 
Original Policy Date
1/8/09
Last Review Status/Date
Reviewed with literature search/1:2012
Issue
1:2012
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is frequently overexpressed and activated in non-small-cell lung cancer (NSCLC). Anti-EGFR drugs that target EGFR include the tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. These targeted therapies block intracellular receptor phosphorylation, dampening signal transduction through pathways downstream to the EGF receptor, such as the RAS/RAF/MAPK cascade. RAS proteins are G-proteins that cycle between active and inactive 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 important in cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.

The KRAS gene (which encodes for the RAS proteins) can harbor oncogenic mutations that result in a constitutively activated protein, independent of signaling from the EGF receptor, possibly rendering a tumor resistant to therapies that target the EGF receptor.

TKIs
Two TKIs are used to treat NSCLC: erlotinib and gefitinib.

Erlotinib (Tarceva®) received approval from the U.S. Food and Drug Administration (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. Gefitinib (Iressa®) was approved by the FDA 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 2 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 further 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 U.S. in 2005, it continued to be used elsewhere in the world, and a 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 U.S. (1) All of the patients had advanced or metastatic disease and had been previously treated with at least 1 platinum-containing regimen, and were randomized to receive either gefitinib or docetaxel. Of the 1,466 patients, 1,433 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 stated that based on their findings, they are hopeful that gefitinib can return as a treatment for lung cancer in the U.S. 

Because gefitinib is currently in very limited use in the U.S., and only as part of a special access program, this policy will only address studies that assess the response to erlotinib in relation to the presence or absence of KRAS mutations in NSCLC. 

Anti-EGFR monoclonal antibodies
Anti-EGFR monoclonal antibodies include cetuximab and panitumumab. Recent conclusive evidence has shown that patients with metastatic colorectal cancer whose tumors harbor KRAS mutations do not respond to EGFR monoclonal antibodies, as summarized in a TEC Assessment. (2) Cetuximab is used in combination with chemotherapy in patients with advanced or recurrent NSCLC as first-line and maintenance therapy.
 

KRAS mutation analysis is commercially available to test NSCLC, and laboratories performing the test include Genzyme Genetics and Medical Solutions™. 

Several studies have shown that EGFR and KRAS mutations are mutually exclusive. (3) Although several of the studies outlined in this policy that analyzed KRAS mutations also tested for other markers in NSCLC (e.g., EGFR mutations), only the data from each study as they relate to KRAS are presented in the policy. 

See policy 2.04.45 for epidermal growth factor receptor [EGFR] mutation analysis for patients with non-small cell lung cancer [NSCLC], and policy  2.04.53 for KRAS mutation analysis in metastatic colorectal cancer.  


Policy 

Analysis of somatic mutations of the KRAS gene is considered investigational as a technique to predict treatment non-response to anti-EGFR therapy with the tyrosine-kinase inhibitor erlotinib and the anti-EGFR monoclonal antibody cetuximab in non-small-cell lung carcinoma. 


Policy Guidelines

Effective in 2012, there is CPT coding for KRAS testing:

81275: KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene)(e.g., carcinoma) gene analysis, variants in codons 12 and 13

81403: Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) – includes KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene)(e.g., carcinoma) gene analysis, variants on exon 3 (e.g., codon 61).

Prior to 2012, there were no specific CPT codes for KRAS mutation analysis. Multiple codes describing genetic analysis would likely be used (e.g., codes from 83890-83912).

There is a HCPCS “S” code that is specific to KRAS mutation analysis:

S3713: KRAS mutation analysis testing.

Effective in 2011, there is a CPT code for using archival tissue for analyses such as this:

88363: Examination and selection of retrieved archival (i.e., previously diagnosed) tissue(s) for molecular analysis (e.g., KRAS mutational analysis).


Benefit Application
BlueCard/National Account Issues

No applicable information 


Rationale

KRAS and EGFR tyrosine kinase inhibitors (TKIs) 

Data on the role of KRAS mutations in non-small-cell lung cancer (NSCLC) and response to erlotinib are available from 2 Phase III trials that conducted nonconcurrent subgroup analyses of the efficacy of tyrosine-kinase inhibitors (TKIs) in patients with wild-type (nonmutated) versus mutated KRAS lung tumors, Phase II trials, retrospective single-arm studies, and two meta-analyses. 

Pao and colleagues were the first to suggest that patients with KRAS-mutated lung tumors were nonresponsive to treatment with EGFR TKIs. (4) Thirty-six patients with bronchioloalveolar carcinoma underwent KRAS mutation analysis; 9 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 9 patients with KRAS-mutated tumors responded to erlotinib (p =0.5531).

Zhu and colleagues performed a nonconcurrent 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. (5) 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. (6) 

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 1 patient (5.0%) responded (hazard ratio [erlotinib vs. placebo] 1.67 [95% CI: 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 and colleagues performed a nonconcurrent 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. (7) The original Phase III trial (TRIBUTE study) randomized patients to carboplatin and paclitaxel either with erlotinib or with placebo. (8) 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 and colleagues evaluated the treatment response to erlotinib in chemotherapy-naive patients 70 years of age or older who had advanced NSCLC. (9) 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 6 patients with a KRAS mutation responded to erlotinib, whereas 5 of 35 (14%) patients with wild-type KRAS had a partial response.

In a Phase II trial, Miller and colleagues compared response to erlotinib in 101 patients with lung bronchioloalveolar carcinoma (n =12) or adenocarcinoma, bronchioloalveolar subtype (n =89), according to KRAS mutational status. (10) Of the patients with evaluable tumor, 18 patients (18%) had KRAS-mutated tumors, and none of them responded to erlotinib (0 of 18; 95% CI: 0% to 19%; p < 0.01). Response rate was 32% in patients without 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 and colleagues studied response to erlotinib in 53 chemotherapy-naive patients with advanced NSCLC. (11) Histologic material was available to assess KRAS mutational status from 29 patients, 10 of whom had mutations. All 10 were nonresponders to erlotinib (p =0.125). 

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 tyrosine kinase inhibitors (erlotinib or gefitinib). (12) 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 tyrosine kinase inhibitor 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 them 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 non-small cell carcinoma, involving 7,043 patients in 52 countries. (13) 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 and overall survival was of borderline statistical significance. The authors concluded that current data do not support selection of patients for treatment with erlotinib on the basis of tumor molecular characteristics and that further studies are needed to determine definitively whether patients with KRAS mutations can derive survival benefit from erlotinib.

Two meta-analyses have been performed on the relationship between KRAS mutations and response to EGFR TKI therapy, and are outlined below. Data were insufficient to make a determination about an association between KRAS mutation status and PFS or OS in these meta-analyses.

Linardou and colleagues performed a meta-analysis which included 17 studies with 1,008 patients, 165 of whom (16.4%) had a KRAS mutation. (14) Eligible studies had to report response (complete or partial) stratified by KRAS mutational status. The studies were also stratified by ethnicity, which of the TKIs patients received (studies included gefitinib and/or erlotinib), response criteria, possible selection bias and previous treatment if any. No significant difference was noted between subgroups in terms of response in the presence of a KRAS mutation. The presence of a KRAS mutation was associated with an absence of response to TKIs (sensitivity =0.21 [95% CI: 0.16-0.28], specificity =0.94 [0.89 -0.97]; positive likelihood ratio =3.52; negative likelihood ratio =0.84). (For the analysis, likelihood ratios were calculated by using pooled estimates for sensitivity and specificity). The authors conclude that their comprehensive review showed that KRAS mutations confer a high level of resistance to anti-EGFR therapies but that limitations exist, including a lack of individual patient data which renders conclusions tentative, and that prospective validation should be done. Furthermore, the inadequate reporting of survival data precluded meaningful assessment of the effect of KRAS mutations on survival. Additional limitations to the analysis include the heterogeneity of response endpoints, differences in treatment regimens, patient selection criteria and the retrospective nature of the analyzed series.

Mao and colleagues performed a meta-analysis which included 22 studies, with a total of 1,470 patients with NSCLC (1,335 patients were evaluable for response), of whom 231 (16%) had KRAS mutations. (15) Patient populations were heterogeneous with respect to smoking history, tumor histology, stage, ethnicity, treatment received and response criteria. The primary endpoint was objective response rate, defined as the sum of complete and partial response. The objective response rates for patients with a KRAS mutation and wild-type KRAS were 3% and 26%, respectively. Inadequate reporting of survival data precluded meaningful assessment of the effect of KRAS status on survival in NSCLC patients treated with EGFR-TKIs. Data for PFS and OS stratified by KRAS status were available in 8 studies. The median PFS in KRAS mutant and wild-type patients was 3.0 months and 3.9 months, respectively. The median OS in KRAS mutant and wild-type patients was 4.7 months and 10.7 months, respectively. However, only 2 studies presented data on hazard ratio with 95% CI for PFS and OS, and therefore, a pooled analysis for hazard ratio was not performed. 

KRAS and anti-EGFR monoclonal antibodies

Two Phase III trials, BMS-099 and FLEX, investigated platinum-based chemotherapy with and without cetuximab in the first-line setting for advanced NSCLC. Subsequently, an investigation of KRAS mutational status and cetuximab treatment has been performed from both trials.

In the multicenter Phase III trial BMS099, 676 chemotherapy-naïve patients with stage IIIB or IV NSCLC were assigned to taxane and carboplatin with or without cetuximab. (16) The primary end point was PFS, overall response rate, OS, quality of life and safety. The addition of cetuximab did not significantly improve PFS, however there was a statistically significant improvement in overall response rate in the cetuximab group. There was a trend in OS favoring cetuximab, however, it did not reach statistical significance. Subsequently, a retrospective, correlative analysis of this trial was conducted to identify molecular markers for the selection of patients most likely to benefit from cetuximab. (17) Of the original 676 patients enrolled, 202 (29.9%) had tumor samples available for KRAS testing. KRAS mutations were present in 35 patients (17%). Among patients with wild-type KRAS, OS was similar between the cetuximab-containing arm (n =85) and the chemotherapy alone arm (n =82) (HR 0.93; 95% CI: 0.67-1.30; p =0.68; median survival time of 9.7 and 9.9 months, respectively). Among patients with KRAS mutations, OS was similar between the cetuximab-containing arm (n =13) and the chemotherapy alone arm (n =22) (HR 0.907; 95% CI: 0.45-2.07; p =0.93; median survival time of 16.8 and 10.8 months, respectively). Overall, the study showed no significant treatment-specific interactions between the presence of KRAS mutations and the outcomes evaluated, and differences that favored the addition of cetuximab in the KRAS mutant subgroup were consistent with those observed in patients with wild-type KRAS and in the overall study population. The authors concluded that interpretation of the data should be with caution given the small subgroup sample size and retrospective nature of the analysis, but that the results do not appear to show a similar correlation with the lack of cetuximab benefit established in patients with KRAS mutated metastatic colorectal cancer.

In the open-label randomized Phase III FLEX trial, 1,125 patients with stage III or IV chemotherapy-naïve NSCLC were randomly assigned to receive either chemotherapy (cisplatin and vinorelbine) plus cetuximab (n =557) or chemotherapy alone (n =568). (18) The primary endpoint was OS. The patients who received chemotherapy plus cetuximab survived longer than those in the chemotherapy-only group (median 11.3 months versus 10.1 months; HR for death 0.871 [95% CI: 0.762-0.996]; p =0.04). Subsequently, of the patients for whom KRAS status could be determined (395 of 1,125 or 35%), KRAS mutation status was performed on archival tumor tissue. (19) The results, which are only available in abstract form, reported a KRAS mutation in 75 of the 395 tumor samples (19%). Among the patients with a KRAS mutation, OS in the cetuximab-containing arm (n =38) versus the chemotherapy-alone arm (n =37) was similar (HR 1.00; 95% CI: 0.60-1.66; p =1.0; median survival time of 8.9 months versus 11 months respectively). Among patients with wild-type KRAS, OS in the cetuximab-containing arm (n =161) versus the chemotherapy-alone arm (n =159) was similar (HR, 0.96; 95%CI, 0.75-1.66; p =1.23; median survival time of 11.4 months versus 10.3 months respectively).

PFS observed between in the cetuximab-containing and chemotherapy alone arms were similar between patients with mutant and wild-type KRAS. Response rates in the cetuximab-containing arm in patients with KRAS mutant and wild-type tumors were 36.8% and 37.3%, respectively (p =0.96). Overall, the outcome with cetuximab was observed regardless of KRAS mutational status.

National Cancer Institute Clinical Trials Database (PDQ®) and Clinicaltrials.gov

KRAS and EGFR tyrosine kinase inhibitors (TKIs)

A Phase III trial is currently actively assessing overall survival with the combination regimen of ARQ 197 (tivantinib, a novel MET inhibitor) plus erlotinib versus placebo plus erlotinib for the treatment of locally advanced or metastatic non-squamous, non-small cell lung cancer in patients who have received 1 or 2 prior systemic anti-cancer therapies. (NCT01244191) EGFR and KRAS mutation status will be collected prior to randomization. Estimated enrollment is 988, with an estimated study completion date of July 2013.

KRAS and anti-EGFR monoclonal antibodies

A Phase III randomized trial is actively assessing carboplatin and paclitaxel with or without bevacizumab and/or cetuximab in treating patients with stage IV or recurrent NSCLC. (NCT00946712) Primary outcomes are PFS and OS, and one secondary outcome is to evaluate the role of KRAS mutations in terms of cetuximab efficacy. Expected enrollment is 1,546, with an estimated trial completion date of June 2012.

Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) Guidelines (20)

NCCN guidelines state that KRAS mutations are associated with intrinsic TKI resistance, and KRAS gene sequencing could be useful for the selection of patients as candidates for TKI therapy, but make no specific recommendations.

No recommendation for KRAS testing is made in the NCCN guidelines as to the use of cetuximab in patients with NSCLC.

Summary

It remains unclear whether assessment of KRAS mutation status will be clinically useful with regard to anti-EGFR therapy in the treatment of non-small-cell lung cancer (NSCLC).

KRAS and EGFR tyrosine kinase inhibitors (TKI)

Data on the role of KRAS mutations in NSCLC and response to erlotinib are available from 2 Phase III trials that conducted non-concurrent subgroup analyses of the efficacy of TKIs in patients with wild-type (non-mutated) versus mutated KRAS lung tumors, Phase II trials, retrospective single-arm studies, and 2 meta-analyses. Although studies have shown that a KRAS mutation in patients with NSCLC confers a high level of resistance to TKIs, data are insufficient to make a determination about an association between KRAS mutation status and survival in these patients.

KRAS and anti-EGFR monoclonal antibodies

A lack of response to the EGFR monoclonal antibodies has been established in metastatic colorectal cancer, and the use of these drugs is mostly restricted to patients with wild-type KRAS. The expectation that KRAS mutation status would also be an important predictive marker for cetuximab use in NSCLC has not been shown. In 2 randomized trials with non-concurrent subgroup analyses of KRAS mutation status and the use of cetuximab with chemotherapy, KRAS mutations did not appear to identify patients who would not benefit from anti-EGFR antibodies, as the outcomes observed with cetuximab were regardless of KRAS mutational status.

Future challenges

An editorial (21) highlights the challenges in biomarker testing and validation in patients with NSCLC, as summarized here. First, the purest evaluation of a biomarker would be from a study of treatment compared with observation or placebo, allowing for the assessment of the prognostic importance of the marker in the untreated control arm and the assessment of the predictive effect by comparing the treated and untreated arms. However, it is not feasible to conduct placebo-controlled studies in first-, second- or third-line treatment of NSCLC, as agents of proven benefit are available. Therefore, studies must compare targeted agents with another treatment or must add the targeted therapy to a standard therapy. A further confounding factor is that the effect of the standard therapy may also be different in the biomarker subsets. Finally, many of the studies of targeted therapies suffer from crossover at the time of disease progression, making assessment of overall survival extremely difficult.

The results of ongoing Phase III trials may guide the future management of NSCLC with TKIs and anti-EGFR monoclonal antibodies according to KRAS mutational status.

 

References:

  1. Kim ES, Hirsh V, Mok T 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.
  2. 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.
  3. Toschi L, Cappuzzo F. Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors. Oncologist 2007; 12(2):211-20.
  4. Pao W, Wang TY, Riely GJ et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005; 2(1):57-61.
  5. 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.
  6. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353(2):123-32.
  7. 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.
  8. Herbst RS, Prager D, Hermann R 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. J Clin Oncol 2005; 23(25):5856-8.
  9. 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.
  10. 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.
  11. 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):6049-55.
  12. 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.
  13. 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. J Thorac Oncol 2008; 3(12):1446-53.
  14. 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 Oncol 2008; 9(10):962-72.
  15. Mao C, Qiu LX, Liao RY et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 2010; 69(3):272-8.
  16. Lynch TJ, Patel T, Dreisbach L et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: Results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010; 28(6):911-7.
  17. Khambata-Ford S, Harbison CT, Hart LL et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010; 28(6):918-27.
  18. Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open-label randomized phase III trial. Lancet 2009; 373(9674):1525-31.
  19. Gatzemeier U, Paz-Ares L, Rodrigues R et al. Molecular and clinical biomarkers of cetuximab efficacy: data from the phase III FLEX study in non-small cell lung cancer (NSCLC). J Thorac Oncol 2009; 4:S324 (suppl 1; abstr B2.3).
  20. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. (v.2.2011). Available online at http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Last accessed December 2010.
  21. Shepherd FA, Tsao MS. Epidermal growth factor receptor biomarkers in non-small-cell lung cancer: a riddle, wrapped in a mystery, inside an enigma. J Clin Oncol 2010; 28(6):903-5.

 

Codes

Number

Description

CPT  81275 KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene)(e.g., carcinoma) gene analysis, variants in codons 12 and 13
  81403 Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) – includes KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene)(e.g., carcinoma) gene analysis, variants on exon 3 (e.g., codon 61)
ICD-9-CM Diagnosis    Investigational for all relevant diagnoses
HCPCS S3713 KRAS mutation analysis testing
ICD-10-CM (effective 10/1/13)   Investigational for all relevant diagnoses
  C34.0 -C34.92 Malignant neoplasm of bronchus and lung code range
ICD-10-PCS (effectve 10/1/13)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.


Index

KRAS Mutation Testing
K-ras

Policy History
Date Action Reason
1/08/09 Add to Medicine section New policy
01/14/10 Replace policy Policy updated with literature search; no change to policy statement. References 12-14 added
01/13/11 Replace policy Policy updated with literature search; changes to policy statement to indicate that testing to predict non-response to anti-EGFR monoclonal antibody (cetuximab) is also investigational. Reference numbers 14-19 and 21 added; reference 20 updated
1/12/12 Replace policy Policy updated with literature search; no change to policy statement. No references added