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Molecular Analysis for Targeted Therapy of Non-Small-Cell Lung Cancer (NSCLC)

Policy Number: MP-468

Latest Review Date: October 2019

Category: Laboratory

Policy Grade: B

POLICY:

Effective for dates of service on or after October 25, 2019:

EGFR Testing

Except as noted below, analysis of somatic variants 18 through 21 (e.g., G719X, L858R, T790M, S6781, L861Q) within the EGFR gene may be considered medically necessary to predict treatment response to EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib [Tarceva®}, gefitinib [Iressa®], afatinib [Gilotrif®], or osimertinib [Tagrisso™]) in patients with:

  • In patients with advanced lung adenocarcinoma; OR
  • Large cell carcinoma; OR
  • Advanced squamous cell NSCLC; OR
  • NSCLC not otherwise classified

Analysis for other EGFR variants within exons 22-24, or other applications related to NSCLC, is considered not medically necessary and investigational.

*Reference Medical Policy 256: Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy) for information regarding circulating tumor DNA (ctDNA) in NSCLC.

ALK Testing

Analysis of somatic rearrangement variants of the ALK gene may be considered medically necessary as a technique to predict treatment response to ALK inhibitor therapy (for example, crizotinib [Xalkori®], ceritinib [Zykadia™] , alectinib [Alecensa®], or brigatinib [Alunbrig™]) for the following:

  • In patients with advanced lung adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded.

Analysis of somatic rearrangement variants of the ALK is considered not medically necessary and investigational in all other situations.

BRAF V600E Testing

Analysis of the BRAF V600E variant may be considered medically necessary to predict treatment response to BRAF or MEK inhibitor therapy (e.g., dabrafenib [Tafinlar®] and trametinib [Mekinist®]) for the following:

  • In patients with advanced lung adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded.

ROS1 Testing

Analysis of somatic rearrangement variants of the ROS1 gene may be considered medically necessary to predict treatment response to ALK inhibitor therapy (crizotinib [Xalkori®]) for the following:

  • In patients with advanced lung adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded

KRAS Testing

Analysis of somatic variants of the KRAS gene is considered not medically necessary and investigational as a technique to predict treatment non-response to anti-EGFR therapy with the tyrosine-kinase inhibitors and the anti-EGFR monoclonal antibody cetuximab in NSCLC.

NTRK GENE FUSION Testing

Analysis of NTRK gene fusions may be considered medically necessary to predict treatment response to larotrectinib for the following:

  • In patients with advanced lung adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded

Other Genes

Analysis for genetic alterations in the genes RET, MET, and HER2, for the targeted therapy in patients with NSCLC, is considered not medically necessary and investigational.

TUMOR MUTATIONAL BURDEN Testing

Analysis of tumor mutational burden (TMB) for targeted therapy in patients with NSCLC is considered not medically necessary and investigational.


Effective for dates of service November 13, 2018 through October 24, 2019:

EGFR Testing

Except as noted below, analysis of somatic variants 18 through 21 (e.g., G719X, L858R, T790M, S6781, L861Q) within the EGFR gene may be considered medically necessary to predict treatment response to EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib [Tarceva®}, gefitinib [Iressa®], afatinib [Gilotrif®], or osimertinib [Tagrisso™]) in patients with:

  • In patients with advanced lung adenocarcinoma; OR
  • Advanced squamous cell NSCLC

Analysis for other EGFR variants within exons 22-24, or other applications related to NSCLC, is considered not medically necessary and investigational.

*Reference Medical Policy 256: Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy) for information regarding circulating tumor DNA (ctDNA) in NSCLC.

ALK Testing

Analysis of somatic rearrangement variants of the ALK gene may be considered medically necessary as a technique to predict treatment response to ALK inhibitor therapy (for example, crizotinib [Xalkori®], ceritinib [Zykadia™] , alectinib [Alecensa®], or brigatinib [Alunbrig™]) for the following:

  • In patients with advanced adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded.

Analysis of somatic rearrangement variants of the ALK is considered not medically necessary and investigational in all other situations.

BRAF V600E Testing

Analysis of the BRAF V600E variant may be considered medically necessary to predict treatment response to BRAF or MEK inhibitor therapy (e.g., dabrafenib [Tafinlar®] and trametinib [Mekinist®]) for the following:

  • In patients with advanced lung adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded.

ROS1 Testing

Analysis of somatic rearrangement variants of the ROS1 gene may be considered medically necessary to predict treatment response to ALK inhibitor therapy (crizotinib [Xalkori®]) for the following:

  • In patients with advanced lung adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded

KRAS Testing

Analysis of somatic variants of the KRAS gene is considered not medically necessary and investigational as a technique to predict treatment non-response to anti-EGFR therapy with the tyrosine-kinase inhibitors and the anti-EGFR monoclonal antibody cetuximab in NSCLC.

Other Genes

Analysis for genetic alterations in the genes RET, MET, and HER2, for the targeted therapy in patients with NSCLC, is considered not medically necessary and investigational.


Effective for dates of service October 27, 2017 through November 13, 2018:

EGFR Testing

Except as noted below, analysis of two types of somatic variants within the EGFR gene -- small deletions in exon 19 and a point variant in exon 21 (L858R) – – may be considered medically necessary to predict treatment response to EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib [Tarceva®}, gefitinib [Iressa®], afatinib [Gilotrif®], or

  • In patients with advanced lung adenocarcinoma; or
  • In patients whom an adenocarcinoma component cannot be excluded

Analysis for the T790M mutation variants in the gene for the EGFR – may be considered medically necessary as a technique to predict treatment response to osimertinib (Tagrisso™) for the following: in patients with:

  • In patients who have progressed on or after EGFR-TKI therapy
  • In patients with advanced lung adenocarcinoma; OR
  • Advanced squamous cell NSCLC

Analysis of two types of somatic mutation variants within the EGFR gene – small deletions in exon 19 and a point mutation variant in exon 21 (L858R) - is considered not medically necessary and investigational for patients with advanced NSCLC of squamous cell-type.

Analysis for other EGFR variants within exons 18-24, or other applications related to NSCLC, is considered not medically necessary and investigational.

ALK Testing

Analysis of somatic rearrangement variants of the ALK gene may be considered medically necessary as a technique to predict treatment response to ALK inhibitor therapy (for example, crizotinib [Xalkori®], ceritinib [Zykadia™] , alectinib [Alecensa®], or brigatinib [Alunbrig™]) for the following:

  • In patients with advanced adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded.

Analysis of somatic rearrangement variants of the ALK gene in all other applications is considered not medically necessary and investigational.

BRAF V600E Testing

Analysis of the BRAF V600E variant may be considered medically necessary to predict treatment response to BRAF or MEK inhibitor therapy (e.g., dabrafenib [Tafinlar®] and trametinib [Mekinist®]) for the following:

  • In patients with advanced lung adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded.

ROS1 Testing

Analysis of somatic rearrangement variants of the ROS1 gene may be considered medically necessary to predict treatment response to ALK inhibitor therapy (crizotinib [Xalkori®]) for the following:

  • In patients with advanced lung adenocarcinoma; OR
  • In patients whom an adenocarcinoma component cannot be excluded

KRAS Testing

Analysis of somatic variants of the KRAS gene is considered not medically necessary and investigational as a technique to predict treatment non-response to anti-EGFR therapy with the tyrosine-kinase inhibitors and the anti-EGFR monoclonal antibody cetuximab in NSCLC.

Other Genes

Analysis for genetic alterations in the genes including but not limited to RET, MET, and HER2, for the targeted therapy in patients with NSCLC, is considered not medically necessary and investigational.


Effective for dates of service on or after January 13, 2017 through October 26, 2017:

EGFR Gene

Analysis of two types of somatic mutation within the EGFR gene -- small deletions in exon 19 and a point mutation in exon 21 (L858R) – may be considered medically necessary to predict treatment response to EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib [Tarceva®}, gefitinib [Iressa®], or afatinib [Gilotrif®], for the following:

  • In patients with advanced lung adenocarcinoma; or
  • In patients whom an adenocarcinoma component cannot be excluded

Analysis for the T790M mutation in the gene for the EGFR may be considered medically necessary as a technique to predict treatment response to osimertinib (Tagrisso™) for the following:

  • In patients who have progressed on or after EGFR-TKI therapy
  • Analysis of two types of somatic mutation within the EGFR gene – small deletions in exon 19 and a point mutation in exon 21 (L858R) - is considered not medically necessary and investigational for patients with advanced NSCLC of squamous cell-type.

Analysis for other EGFR mutations within exons 18-24, or other applications related to NSCLC, is considered not medically necessary and investigational.

KRAS Gene

Analysis of somatic mutations of the KRAS gene is considered not medically necessary and investigational as a technique to predict treatment non-response to anti-EGFR therapy with the tyrosine-kinase inhibitors and the anti-EGFR monoclonal antibody cetuximab in NSCLC.

ALK Gene

Analysis of somatic rearrangement mutations of the ALK gene may be considered medically necessary as a technique to predict treatment response to ALK inhibitor therapy (for example, crizotinib [Xalkori®] or ceritinib [Zykadia™]) for the following:

  • In patients with advanced adenocarcinoma; or
  • In patients whom an adenocarcinoma component cannot be excluded.

Analysis of somatic rearrangement mutations of the ALK gene in all other applications is considered not medically necessary and investigational.

Other Genes

Analysis for genetic alterations in other genes including but not limited to ROS, RET, MET, BRAF, and HER2, for the targeted therapy in patients with NSCLC, is considered not medically necessary and investigational.


Effective for dates of service October 1, 2014 through January 12, 2017:

EGFR Gene

Analysis of two types of somatic mutation within the EGFR gene -- small deletions in exon 19 and a point mutation in exon 21 (L858R) – may be considered medically necessary to predict treatment response to erlotinib or afatinib for the following:

  • In patients with advanced lung adenocarcinoma; or
  • In patients whom an adenocarcinoma component cannot be excluded

Analysis of two types of somatic mutation within the EGFR gene – small deletions in exon 19 and a point mutation in exon 21 (L858R) - is considered not medically necessary and investigational for patients with advanced NSCLC of squamous cell-type.

Analysis for other EGFR mutations within exons 18-24, or other applications related to NSCLC, is considered not medically necessary and investigational.

KRAS Gene

Analysis of somatic mutations of the KRAS gene is considered not medically necessary and investigational as a technique to predict treatment non-response to anti-EGFR therapy with the tyrosine-kinase inhibitors and the anti-EGFR monoclonal antibody cetuximab in NSCLC.

ALK Gene

Analysis of somatic rearrangement mutations of the ALK gene may be considered medically necessary as a technique to predict treatment response to crizotinib for the following:

  • In patients with advanced adenocarcinoma; or
  • In patients whom an adenocarcinoma component cannot be excluded.

Analysis of somatic rearrangement mutations of the ALK gene in all other applications is considered not medically necessary and investigational.

Other Genes

Analysis for genetic alterations in other genes including but not limited to ROS, RET, MET, BRAF, and HER2, for the targeted therapy in patients with NSCLC, is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Over half of patients with non-small-cell lung cancer (NSCLC) present with advanced and therefore incurable disease; treatment in this setting has been with platinum-based chemotherapy. The identification of specific, targetable oncogenic “driver mutations” in a subset of NSCLCs has resulted in a reclassification of lung tumors to include molecular subtypes that may direct targeted therapy depending on the presence of specific variants.

Non-Small-Cell Lung Cancer

Treatment options for NSCLC depend on disease stage and include various combinations of surgery, radiation therapy, systemic therapy, and best supportive care. Unfortunately, in up to 85% of cases, the cancer has spread locally beyond the lungs at diagnosis, precluding surgical eradication. Also, 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 eight to 11 months and a one- year survival of 30% to 45%. The identification of specific, targetable oncogenic “driver” mutations in a subset of NSCLCs has resulted in a reclassification of lung tumors to include molecular subtypes, which are predominantly of adenocarcinoma histology. Testing for EGFR variants and ALK rearrangements in clinical decision making for the treatment of NSCLC is routine. The use of testing for other variants to direct targeted therapy continues to evolve.

EGFR Gene

The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (TK), is frequently overexpressed and activated in NSCLC. Drugs that inhibit EGFR signaling either prevent ligand binding to the extracellular domain (monoclonal antibodies) or inhibit intracellular TK activity (small molecule TKIs). These targeted therapies dampen signal transduction through pathways downstream to the EGFR, such as the RAS/RAF/MAPK cascade. RAS proteins are G-proteins that cycle between active and inactive forms in response to stimulation from cell surface receptors such as EGFR, acting as binary switches between cell surface EGFR and downstream signaling pathways. These pathways are important in cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.

Variants in two regions of the EGFR gene (exons 18-24), small deletions in exon 19, and a point variant in exon 21 (L858R), appear to predict tumor response to TKIs such as erlotinib. Likewise, tumors with an acquired exon 20 (T790M) substitution variant appear to respond to osimertinib following failure of TKI therapy.

The prevalence of EGFR variants in NSCLC varies by population, with the highest prevalence in non-smoking Asian women, with adenocarcinoma, in whom EGFR variants have been reported to be up to 30% to 50%. The reported prevalence in the white population is approximately 10%.

ALK Gene

Anaplastic lymphoma kinase (ALK) is a TK that, in NSCLC, is aberrantly activated because of a chromosomal rearrangement which leads to a fusion gene and expression of a protein with constitutive tyrosine kinase activity that has been demonstrated to play a role in controlling cell proliferation. The EML4-ALK fusion gene results from an inversion within the short arm of chromosome 2.

The EML4-ALK rearrangement (“ALK-positive”) is detected in 3% to 6% of NSCLC patients, with the highest prevalence in never-smokers or light ex-smokers who have adenocarcinoma.

BRAF Gene

RAF proteins are serine/threonine kinases that are downstream of RAS in the RAS-RAF-ERK-MAPK pathway. In this pathway, the BRAF gene is the most frequently mutated in NSCLC, in approximately 1% to 3% of adenocarcinomas. Unlike melanoma, about 50% of the variants in NSCLC are non-V600E variants. Most BRAF variants occur more frequently in smokers.

ROS1 Gene

ROS1 codes for a receptor TK of the insulin receptor family, and chromosomal rearrangements result in fusion genes. The prevalence of ROS1 fusions in NSCLC varies from 0.9% to 3.7%. Patients with ROS1 fusions are typically never smokers with adenocarcinoma.

KRAS Gene

The KRAS gene (which encodes RAS proteins) can harbor oncogenic variants that result in a constitutively activated protein, independent of signaling from the EGFR, possibly rendering a tumor resistant to therapies that target the EGFR. Variants in the KRAS gene, mainly codons 12 and 13, have been reported in 20% to 30% of NSCLC, and occur most often in adenocarcinomas in heavy smokers.

EGFR, ALK, ROS1, and KRAS driver mutations are considered to be mutually exclusive.

HER2 Gene

Human epidermal growth factor receptor 2 (HER2) is a member of the HER (EGFR) family of TK receptors and has no specific ligand. When activated, it forms dimers with other EGFR family members. HER2 is expressed in approximately 25% of NSCLC. HER2 variants are detected mainly in exon 20 in 1% to 2% of NSCLC, predominantly in adenocarcinomas in nonsmoking women.

RET Gene

RET (rearranged during transfection) is a proto-oncogene that encodes a receptor TK growth factor. Translocations that result in fusion genes with several partners have been reported. RET fusions occur in 0.6% to 2% of NSCLCs and in 1.2% to 2% of adenocarcinomas.

MET Gene

MET amplification is one of the critical events for acquired resistance in EGFR-mutated adenocarcinomas refractory to EGFR-TKIs.

NTRK Gene Fusions

NTRK gene fusions encode tropomyosin receptor kinase (TRK) fusion proteins that act as oncogenic drivers for solid tumors including lung, salivary gland, thyroid, and sarcoma. It is estimated that NTRK gene fusions occur in 0.2% of patients with NSCLC and do not typically overlap with other oncogenic drivers.

Tumor Mutational Burden

Tumor mutational burden is an emerging biomarker of outcomes with immunotherapy in multiple tumor types, including lung cancer.

Targeted Therapies

Four orally administered EGFR-selective small molecule TKIs have been identified for treating NSCLC: gefitinib (Iressa®, AstraZeneca, Cambridge, England), erlotinib (Tarceva®, OSI Pharmaceuticals, Melville NY)), afatinib (Gilotrif™, Boehringer Ingelheim, Ingelheim, Germany), and osimertinib (Tagrisso; AstraZeneca). Gefitinib, erlotinib, afatinib, and osimertinib currently are approved by the U.S. Food and Drug Administration (FDA) for NSCLC when EGFR status is confirmed through a companion diagnostic test.

Crizotinib is an oral small-molecule TKI which is FDA-approved for patients with locally advanced or metastatic NSCLC who are positive for the ALK or ROS1 gene rearrangements confirmed through a companion diagnostic test. Ceritinib is a potent ALK inhibitor that is approved for ALK-positive patients whose cancer has progressed while taking crizotinib or who could not tolerate crizotinib. Alectinib is a selective ALK inhibitor with high central nervous system penetration that is active against several secondary resistance variants to crizotinib. Brigatinib is also an ALK inhibitor that may be able to overcome a broad range of the resistance mechanisms in patients who have progressed on or are intolerant to crizotinib.

BRAF or MEK inhibition with TKIs (e.g., vemurafenib/dabrafenib or trametinib) was originally approved by the FDA for treatment of unresectable or metastatic melanoma with BRAF V600 variants confirmed through a companion diagnostic test. The combination of dabrafenib and trametinib was approved for treatment of metastatic NSCLC in 2017 for patients with confirmed BRAF V600 variants.

For the treatment of KRAS-mutated NSCLC, EGFR TKIs and anti-EGFR monoclonal antibodies have been investigated as possible treatment options. Anti-EGFR monoclonal antibodies include cetuximab and panitumumab. Cetuximab may be used in combination with chemotherapy in patients with advanced or recurrent NSCLC as first-line and maintenance therapy. Panitumumab is not used in NSCLC.

Larotrectinib was approved in 2018 for the treatment of patients with solid tumors harboring an NTRK gene fusion. There is currently no FDA approved companion diagnostic test for larotrectinib. The clinical review states, "The clinical review team and CDRH agreed that it is in the best interest of U.S. patients to approve larotrectinib before one or more companion diagnostic assays are ready for a PMA submission. LoxoOncology has agreed to a postmarketing commitment to work with diagnostic developers to develop an analytically and clinically validated companion diagnostic test for selection of patients with NTRK fusion-positive solid tumors for whom larotrectinib is safe and effective."

Nivolumab in combination with iplimumab has been investigated as a treatment option for patients with NSCLC with tumor mutational burden (TMB) ≥10 mutations per megabase. There is no FDA companion diagnostic test for TMB.

Targeted therapies currently under investigation and not FDA-approved for the remaining genetic alterations in NSCLC are trastuzumab and afatinib for HER2 variants, crizotinib for MET amplification, and cabozantinib for RET rearrangements.

KEY POINTS:

The most recent literature search was conducted through August 26, 2019.

Summary of Evidence

For individuals who have advanced-stage non-small-cell lung cancer (NSCLC) who are being considered for targeted therapy who receive testing for EGFR variants and ALK rearrangements, the evidence includes Phase III studies comparing tyrosine kinase inhibitors (e.g., afatinib, erlotinib, gefitinib, osimertinib) with chemotherapy. Relevant outcomes are overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. Studies have shown that TKIs are superior to chemotherapy regarding tumor response rate and progression-free survival (PFS), with a reduction in toxicity and improvement in quality of life. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have advanced-stage NSCLC who are being considered for targeted therapy who receive testing for BRAF variants and ROS1 rearrangements, the evidence includes nonrandomized trials and observational studies of BRAF and MEK inhibitors and crizotinib or ceritinib, respectively. Relevant outcomes are overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. Studies have shown that combination therapy with dabrafenib and trametinib for BRAF V600E variant NSCLC and crizotinib for NSCLC with ROS1 rearrangements result in response rates of 60% and 70%, respectively, with acceptable toxicity profiles. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have advanced-stage NSCLC who are being considered for targeted therapy who receive testing for KRAS or HER2 variants, RET rearrangements, or MET amplifications, the evidence includes for KRAS post hoc analyses trials, observational studies, and meta-analyses; for the other variants, the evidence includes a Phase 2 trial with preliminary data, and retrospective analyses of very small case series and case reports. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, quality of life, and treatment-related morbidity. Studies have shown that KRAS variants in patients with NSCLC confer a high level of resistance to TKIs; data are insufficient to assess any additional benefit to testing for KRAS variants to select for EGFR TKIs beyond EGFR testing. In two randomized trials with post hoc analyses of KRAS variant status and use of the anti-EGFR monoclonal antibody cetuximab with chemotherapy, KRAS variants did not identify patients who would benefit from anti-EGFR antibodies, because outcomes with cetuximab were similar regardless of KRAS variant status. In two randomized controlled trials of advanced KRAS-variant positive disease, MEK inhibitors did not improve progression-free survival compared with docetaxel. Studies for HER2, RET, and MET variant testing have reported response rates and progression-free survival in numbers of patients too small from which to draw conclusions. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have advanced-stage NSCLC who are being considered for targeted therapy who receive NTRK gene fusion testing, the evidence includes prospective observational studies. Relevant outcomes are overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. In 55 patients with consecutively and prospectively identified TRK fusion–positive solid tumors, including four patients with lung tumors, the overall response rate was 80% (95% CI, 67 to 90). The median PFS had not been reached after a median follow-up duration of 9.9 months (range, 0.7 to 25.9). Responses were observed regardless of tumor type or age of the patient. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have advanced-stage NSCLC who are being considered for targeted therapy who receive tumor mutational burden (TMB) testing, the evidence includes an RCT and retrospective observational studies. In a subgroup analysis of an ongoing RCT, PFS was significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden (≥10 mutationsper megabase). In exploratory analyses, retrospective observational studies have reported an association between higher TMB and longer PFS and OS in patients receiving immunotherapy. These results need to be confirmed in additional, well-designed prospective studies. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) Guidelines

EGFR Testing

The National Comprehensive Cancer Network (NCCN) guidelines (v.7.2019) for the treatment of metastatic non-small-cell lung cancer (NSCLC) recommend the following on epidermal growth factor receptor (EGFR) testing:

  • EGFR mutation testing is recommended (category 1) in patients with nonsquamous NSCLC (i.e., adenocarcinoma, large cell carcinoma) or in NSCLC not otherwise specified, because erlotinib or afatinib (category 1 for both) is recommended for patients who are positive for EGFR variants.
  • When an EGFR variant is discovered prior to first-line chemotherapy, erlotinib (category 1), afatinib (category 1), dacomitinnib (category 1), gefitinib (category 1), or osimertinib (category 1, preferred) are recommended.
  • When an EGFR variant is discovered during first-line chemotherapy, interrupt or continue chemotherapy, then follow with erlotinib, afatinib, or gefitinib.
  • If progression occurs following first-line treatment, EGFR T790M testing is recommended (category 2A). If T790M-positive, osimertinib (category 1), local therapy, or continuing with erlotinib, afatinib, or gefitinib are recommended (depending on symptoms, the location of metastases, and a number of lesions).
  • Tyrosine kinase inhibitors are not recommended as first-line therapy or subsequent therapy following progression for patients negative for EGFR variants or with unknown EGFR status.
  • In patients with squamous cell carcinoma (SCC), EGFR variant testing should be considered in never-smokers; when histology is assessed using small biopsy specimens (rather than surgically resected samples); or when histology is mixed adenosquamous (category 2A).

ALK Testing

NCCN guidelines (v.7.2019) state the following on ALK-rearrangement testing:

  • ALK-rearrangement testing is recommended (category 1) in patients with nonsquamous NSCLC (i.e., adenocarcinoma, large cell carcinoma) or in NSCLC not otherwise specified.
  • If ALK-positive status is discovered before first-line chemotherapy, alectinib (category 1; preferred), brigatinib (category 1), crizotinib (category 1), or ceritinib (category 1) is recommended.
  • If ALK rearrangement is discovered during first-line chemotherapy, interrupt or complete planned chemotherapy and start alectinib (preferred), brigatinib, crizotinib or ceritinib.
  • If there is progression on first-line therapy, continue alectinib, crizotinib, or ceritinib, switch to ceritinib, alectinib, lorlatinib, or brigatinib, or consider local therapies are recommended (depending on symptoms, the location of metastases, and number of lesions).
  • In patients with SCC, ALK-rearrangement testing should be considered in never-smokers; when histology is assessed using small biopsy specimens (rather than surgically resected samples); or when histology is mixed adenosquamous (category 2A).
  • Flare phenomenon has been seen in a subset of patients who discontinue ALK inhibitors. If disease flare occurs, restart ALK inhibitor.

ROS1 Testing

NCCN guidelines (v.7.2019) state the following on ROS1-rearrangement testing:

  • ROS1-rearrangement testing is recommended (category 2A) in patients with nonsquamous NSCLC (i.e., adenocarcinoma, large cell carcinoma) or in NSCLC not otherwise specified.
  • ROS1-rearrangement testing may be considered in patients with SCC.
  • If ROS1-positive status is discovered, crizotinib (preferred), entrictinib (preferred) or ceritinib is recommended.

BRAF Testing

NCCN guidelines (v.6.2018) state the following on BRAF testing:

  • BRAF testing is recommended (category 2A) in patients with nonsquamous NSCLC (i.e., adenocarcinoma, large cell carcinoma) or in NSCLC not otherwise specified.
  • BRAF testing may be considered in patients with squamous cell carcinoma (SCC).
  • If BRAF V600E variant-positive status is discovered, combination dabrafenib and trametinib or other first-line cytotoxic therapy options are recommended.

KRAS Gene

NCCN guidelines (v.7.2019) state that "The presence of a KRAS mutation is prognostic of poor survival when compared to patients with tumors without KRAS mutation. Mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. Owing to the low probability of overlapping targetable alterations, the presence of a mutation in KRAS may identify patients who will not benefit from further molecular testing." Targeted therapy for patients with the KRAS variants is currently unavailable.

NTRK Gene Fusions

NCCN guidelines (v.7.2019) state the following on NTRK gene fusion testing:

The Panel added a recommendation for NTRK gene fusion testing in patients with metastatic NSCLC based on clinical data and the approval of larotrectinib for patients with NTRK gene fusion-positive disease. The Panel recommends larotrectinib and entrectinib (category 2A) as either first-line or subsequent therapy options for patients with NTRK gene fusion-positive metastatic NSCLC based on data and the FDA approvals.

Tumor Mutational Burden

NCCN guidelines (v.7.2019) state the following on tumor mutational burden testing:

TMB is an evolving biomarker that may be helpful in selecting patients for immunotherapy. There is no consensus on how to measure TMB.

Other Genes

NCCN (v.6.2018) does not give specific recommendations for testing for genetic alterations in the genes RET, MET, or HER2 in NSCLC. However, it states that the following emerging targeted agents are available for patients with one of these specific genetic alterations:

  • High-level MET amplification or MET exon 14 skipping mutation: crizotinib (category 2A)
  • HER2 mutations: ado-trastuzumab emtansine (category 2B)
  • RET rearrangements: cabozantinib or vandetanib (category 2A)

College of American Pathologists et al

The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology (2013) published evidence-based guidelines for molecular testing to select patients with lung cancer for treatment with EGFR and ALK TKI therapy. Based on excellent quality evidence (category A), the guidelines recommended EGFR variant and ALK rearrangement testing in patients with lung adenocarcinoma regardless of clinical characteristics (e.g., smoking history).

In 2018, updated guidelines were published and added new EGFR and ALK recommendations.130 ROS1 testing is recommended for all patients with lung adenocarcinoma irrespective of clinical characteristics (strong recommendation). BRAF, RET, HER2, KRAS, and MET testing are not recommended as routine stand-alone tests but may be considered as part of a larger testing panel or if EGFR, ALK, and ROS1 are negative (expert consensus opinion).

American Society of Clinical Oncology

In 2014, American Society of Clinical Oncology (ASCO) reviewed and endorsed the 2013 College of American Pathologists, International Association for the Study of Lung Cancer, and the Association for Molecular Pathology guidelines, and highlighted three evolving areas: advances in ALK testing methodology, considerations for selecting appropriate populations for molecular testing, and the emergence of other targeted molecular alterations. ASCO recommendations state that testing for EGFR should be prioritized over other molecular markers in lung adenocarcinoma and that after EGFR testing, testing for ALK should be prioritized over other proposed molecular markers in lung adenocarcinomas, for which published evidence is insufficient to support testing guideline development at the present time.

ASCO (2018) reviewed and endorsed, with minor modifications, the 2018 guidelines from College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology (see above). ASCO differed from the guidelines in its recommendation of stand-alone BRAF testing in patients with advanced lung adenocarcinoma, irrespective of clinical characteristics (expert consensus opinion).

ASCO (2017) also updated its evidence-based recommendations on systemic therapy for patients with stage IV NSCLC. Table 1 summarizes the recommendations and associated quality and strength of evidence.

Table 1. Recommendations on Systemic Therapy for Stage IV NSCLC

Recommendation

QOE

SOR

First-line therapy

   

Sensitizing EGFR variants: afatinib, erlotinib, or gefitinib

High

Strong

ALK rearrangements: crizotinib

Intermediate

Moderate

ROS1 rearrangement: crizotinib

Low

Weak

Second-line therapy

   

Sensitizing EGFR variants and T790M resistance variant: osimertinib

High

Strong

ROS1 rearrangement who have not received prior crizotinib: crizotinib

Low

Moderate

BRAF variants who have received prior immune checkpoint therapy: dabrafenib alone or in combination with trametinib

Insufficient

Moderate

NSCLC: non-small cell lung cancer; QOE: quality of evidence; SOR: strength of recommendation.

American College of Chest Physicians Guidelines

American College of Chest Physicians updated its evidence-based clinical practice guidelines on the treatment of stage IV NSCLC in 2013. Based on their review of the literature, the College reported improved response rates, PFS, and toxicity profiles with first-line erlotinib or gefitinib compared with first-line platinum-based therapy in patients with EGFR variants, especially exon 19 deletion and L858R. The college recommended “testing patients with NSCLC for EGFR mutations at the time of diagnosis whenever feasible, and treating with first-line EGFR TKIs if mutation-positive.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

EGFR Mutation Analysis, Epidermal Growth Factor Receptor Mutation Analysis, EGFR , epidermal growth factor receptor, Erlotinib, gefitinib, genetic testing, Iressa, NSCLC, Non-small cell lung cancer, Tarceva, afatinib, lung adenocarcinoma, crizotinib, KRAS Mutation Testing, KRAS, ALK, ROS, RET, MET, BRAF, HER2, Gilotrif, Tagrisso, Xalkori, certinib, Zykadia, alectinib, Alecensa, brigatinib, Alunbrig, dabrafenib, Taflinar, trametinib, Mekinist, therascreen, vysis, ventana, oncomine, oncominedx, cobas, NTRK, NTRK gene fusion testing, TMB, tumor mutational burden testing, TRK fusion proteins, tropomyosin receptor kinase, larotrectinib, nivolumab

APPROVED BY GOVERNING BODIES:

Table 2 summarizes the FDA-approved treatments for patients with NSCLC along with the concurrently approved diagnostic tests.

Table 2. FDA-Approved Treatment for NSCLC and Companion Diagnostic Tests

Treatment

Indication

FDA Approval of Companion Diagnostic Test

Afatinib (Gilotrif)

2013: First line for patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitutions as detected by FDA-approved test

2016: Second line for patients with metastatic squamous NSCLC

2018: First line for patients with nonresistant EGFR variants other than exon 19 or exon 21 NSCLC

2013: therascreen® EGFR Rotor-Gene Q polymerase chain reaction (RGQ PCR) kit (Qiagen, Netherlands)

2017: FoundationOne CDx™ (Foundation Medicine)

Alectinib (Alecensa)

2015: Second line for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant of crizotinib

2017: First line for patients with ALK-positive NSCLC who have not received prior systemic therapy for metastatic disease

2017: FoundationOne CDx™ (Foundation Medicine)

Brigatinib (Alunbrig)

2017: Second line for patients with metastatic ALK-positive NSCLC who have progressed on or are intolerant of crizotinib

Test not specified in FDA approval

Ceritinib (Zykadia)

2014: Second line for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant of crizotinib

2017: First line for patients with ALK-positive metastatic NSCLC

2015: Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems)

2017: FoundationOne CDx™ (Foundation Medicine)

Crizotinib (Xalkori)

2011: Patients with ALK-positive metastatic NSCLC as detected by FDA-approved test

2011: Vysis ALK Break Apart FISH Probe Kit (Abbott Laboratories, Lake Bluff, IL)

2015: Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Tucson, AZ)

2017: FoundationOne CDx™ (Foundation Medicine)

Crizotinib (Xalkori)

2016: Patients with ROS1-positive metastatic NSCLC

2017: Oncomine™ Dx Target Test (Thermo Fisher Scientific, Waltham, MA)

Dacomitinib (Vizimpro)

2018: First line for patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 (L858R) substitutions

Test not specified in FDA approval

Dabrafenib (Tafinlar) plus trametinib (Mekinist)

2017: Used in combination for treatment of patients with metastatic NSCLC with BRAF V600E variant

2017: Oncomine™ Dx Target Test

2017: FoundationOne CDx™ (Foundation Medicine)

Erlotinib (Tarceva)

2013: First line for patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitutions as detected by FDA-approved test

2010: Maintenance for patients with locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based chemotherapy

2004: Second line for patients with locally advanced or metastatic NSCLC

2013: cobas® EGFR Mutation Test (tissue test) (Roche Diagnostics, Indianapolis, IN)

2016: cobas® EGFR Mutation Test v2 (tissue or blood test) (Roche, Diagnostics, Indianapolis, IN)

2017: FoundationOne CDx™ (Foundation Medicine)

Gefitinib (Iressa)

2015: First line for patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitutions as detected by FDA-approved test

2003: Second line for patients with locally advanced or metastatic NSCLC

2015: therascreen® EGFR Rotor-Gene Q polymerase chain reaction (RGQ PCR) kit

2017: Oncomine™ Dx Target Test

2017: FoundationOne CDx™ (Foundation Medicine)

2017: cobas® EGFR Mutation Test (tissue test) (Roche Diagnostics)

Osimertinib (Tagrisso)

2015: Second line for patients with metastatic NSCLC whose tumors have EGFR T790M variants as detected by FDA-approved test, who have not responded to EGFR-blocking therapy

2018: First line for patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R variants

2015: cobas® EGFR Mutation Test v2 (blood test)

2017: FoundationOne CDx™ (Foundation Medicine)

Larotrectinib (Vitrakvi)

2018: Adult and pediatric patients with solid tumors that:

  • have a neurotrophic receptor tyrosine kinase (NTRK)gene fusion without a known acquired resistance mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidity, and
  • have no satisfactory alternative treatments or that have progressed following treatment.

Test not specified in FDA approval

ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; FDA: Food and Drug Administration; FISH: fluorescence in situ hybridization; NSCLC: non-small-cell lung cancer; PCR: polymerase chain reaction

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

81210

BRAF (B-Raf proto-oncogene, serine/threonine kinase) (e.g., colon cancer, melanoma), gene analysis, V600 variant(s)

81235  

EGFR (epidermal growth factor receptor) (e.g., non-small cell lung cancer) gene analysis, common variants (e.g., exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q)

81275

KRAS (Kirsten rat sarcoma viral oncogene) (e.g., carcinoma) gene analysis, variants in exon 2 (e.g., codons 12 and 13)

81276   

; additional variant(s) (e.g., codon 61 and codon 146

81401

Molecular pathology procedure, Level 2 (e.g., 2-10 NSP’s, 1 methylated variant, or 1 somatic variant [typically using non-sequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)—

Includes EML4/ALK (inv(2)) (e.g., non-small cell lung cancer), translocation or inversion analysis

81404 

Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)-

RET (ret proto-oncogene) (e.g., multiple endocrine neoplasia, type 2B and familial medullary thyroid carcinoma), common variants (e.g., M918T, 2647_2648delinsTT, A883F)

81405

Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis)-

Includes KRAS (Kirsten rat sarcoma viral oncogene homolog) (e.g., Noonan syndrome), full gene sequence

Includes RET (ref proto-oncogene) (e.g., multiple endocrine neoplasia, type 2A and familial medullary thyroid carcinoma), targeted sequence analysis (e.g., exons 10, 11, 13-16)

81406

Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)-

BRAF (B-Raf proto-oncogene, serine/threonine kinase) (e.g., Noonan syndrome), full gene sequence

81479 

Unlisted molecular pathology procedure

0022U   

Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence/absence of variants and associated therapy(ies) to consider (Effective 10/01/17)

 

PREVIOUS CODING:

CPT Codes:

88363

Examination and selection of retrieved archival (previously diagnosed) tissue(s) for molecular analysis (e.g., KRAS mutational analysis). (removed effective 11/1/18)

 

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  110. Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. May 2016; 17(5):642-650.
  111. Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF (V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. Oct 2017; 18(10):1307-1316.
  112. Ramalingam S, Yang JC, Lee CK, et al. LBA1_PR: Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts [abstract]. J Thorac Oncol. Apr 2016; 11(4 Suppl):S152.
  113. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. Aug 28 2018.
  114. Rizvi H, Sanchez-Vega F, La K et al. Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-ProgrammedDeath-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. J. Clin. Oncol., 2018 Jan 18; 36(7).
  115. Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter? J Clin Oncol. Mar 10 2013; 31(8):1112-1121.
  116. Robinson SD, O'Shaughnessy JA, Cowey CL, et al. BRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib. Lung Cancer. Aug 2014; 85(2):326-330.
  117. Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase III trial. Lancet Oncol 2012; 13(3):239-46.
  118. Rosell R, Moran T, Queralt C et al.; Spanish Lung Cancer Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361(10):958-67.
  119. 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.
  120. Rulli E, Marabese M, Torri V, et al. Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial. Ann Oncol. Oct 2015; 26(10):2079-2084.
  121. Sadiq AA, Salgia R. MET as a possible target for non-small-cell lung cancer. J Clin Oncol. Mar 10 2013; 31(8):1089-1096.
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  123. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. Mar 23 2011; 3(75):75ra26.
  124. Sequist LV, Yang JC-H, Yamamoto N et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol 2013; 31(27):3327-34.
  125. Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. Feb 2016; 17(2):234-242.
  126. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. Jun 2013; 368(25):2385-2394.
  127. Shaw AT, Kim TM, Crino L, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. Jul 2017; 18(7):874-886.
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  138. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. Jan 11 2018; 378(2):113-125.
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POLICY HISTORY:

Medical Policy Group, February 2010 (3) – KRAS

Medical Policy Group, February 2011 (3)

Medical Policy Administration Committee, February 2011

Available for comment February 24th through April 11, 2011

Medical Policy Group, December 2011 (3): Coding update effective January 2012- added code 81275 -KRAS

Medical Policy Group, January 2012 (3): Updated Key Points, References (2011 Update)

Medical Policy Group, February 2012 (3): Key Points, References, deleted code S3713 - KRAS

Medical Policy Group, November 2012: 2013 Coding Updates: Added Code 81235 and deleted code range 83890-83914, effective 1/1/2013

Medical Policy Group, December 2012 (3): Coding updates effective January 2013, added codes 81403 and 81405, code range 83890 – 83914 deleted - KRAS

Medical Policy Panel, January 2013

Medical Policy Panel, February 2013 - KRAS

Medical Policy Group, February 2013 (1): Update to policy statement with the addition of clarification statement “of non-squamous cell type” to advanced NSCLC for the coverage criteria point; update to Key Points and References; no change in coverage

Medical Policy Group, February 2013 (1): Update to Key Points and Reference; no change to policy statement - KRAS

Medical Policy Panel, February 2014

Medical Policy Group February 2014 (1): Update to Description, Key Points, and References; no change to policy statement - KRAS

Medical Policy Group, February 2014 (1): Update to Policy statement, Key Points, Key Words, Governing Bodies and References related to addition of new drug afatinib and allowing EGFR mutation testing for patients with small biopsy samples or with mixed histology; investigational statements remain the same

Medical Policy Administration Committee

Available for comment February 26 through April 11, 2014

Medical Policy Group, November 2014: 2015 Coding Update – wording change in code 81403 and 81405 - KRAS

Medical Policy panel, March 2015

Medical Policy Group, March 2015 (3): 2015 Updates to Title, Description, Key Points, Key Words, Approved by Governing Bodies, Coding & References; policy section updated to include policy statements regarding KRAS, ALK and other gene alteration analyses. Policy 467 incorporated into this policy; 467 is now archived.

Medical Policy Administration Committee May 2015

Available for comment April 28 through June 11, 2015

Medical Policy Panel, October 2015

Medical Policy Group, October 2015 (3): Updates to Description & Key Points; no change in policy statement

Medical Policy Group, November 2015: 2016 Annual Coding Update. Added new CPT code 81276 to current coding section; moved CPT code 81403 from current coding to previous coding. Revised CPT codes 81275 and 81405.

Medical Policy Panel, October 2016

Medical Policy Group, January 2017 (3): 2016 Updates to Description, Key Points, Governing Bodies, Coding & References sections; updated policy statements to reflect categories of medications and using medication names as examples; added also to policy statements that “Analysis for the T790M mutation in the gene for the EGFR meets Blue Cross and Blue Shield of Alabama’s medical criteria for coverage as a technique to predict treatment response to osimertinib (Tagrisso™) for the following: In patients who have progressed on or after EGFR-TKI therapy”; removed policy statements for dates of service prior to January 1, 2014

Medical Policy Administration Committee January 2017

Available for comment January 14 through February 28, 2017

Medical Policy Group, October 2017: Quarterly Coding Update. Added CPT code 0022U to Current Coding.

Medical Policy Panel, October 2017

Medical Policy Group, October 2017 (3): 2017 Updates to Description, Key Points, Approved by Governing Bodies & References; policy statements updated to reflect adding coverage criteria for BRAF and ROS variants; also added new available pharmaceuticals to statements

Medical Policy Administration Committee December 2017

Available for comment October 27 through December 10, 2017

Medical Policy Panel, October 2018

Medical Policy Group, November 2018 (9): 2018 Updates to Description, Key Points, Approved by Governing Bodies, References. Policy statement updated, coverage expanded to support testing for additional variants in the EGFR gene, policy statements on other variants unchanged. Removed CPT code 88363 from policy and placed to previous coding section of policy.

Available for comment November 13, 2018 through December 28, 2018

Medical Policy Committee December 2018.

Medical Policy Group September 2019 (9): policy statement updated for clarification: Reference Medical Policy 256: Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy) for information regarding circulating tumor DNA (ctDNA) in NSCLC. No change to policy intent.

Medical Policy Panel, October 2019

Medical Policy Group, October 2019 (9): 2019 Updates to Description, Key Points, References. Removed CPT Codes: 83890-83914 and 81403 from Previous Coding Section. Added CPT Code 81210 to Current Coding Section. Added key words: NTRK, NTRK gene fusion testing, TMB, tumor mutational burden testing, TRK fusion proteins, tropomyosin receptor kinase, larotrectinib, nivolumab. Added medically necessary statement to policy for NTRK gene fusion testing, added investigational statement for TMB testing. No change to policy intent for other variants. Available for comment October 25, 2019 through December 19, 2019.

Medical Policy Administration Committee, November 2019.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.