| Coverage Policy Manual | |
| Policy #: | 2015002 |
| Category: | Laboratory |
| Initiated: | January 2015 |
| Last Review: | November 2023 |
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| Genetic Test: Somatic Biomarker testing (including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB) | |
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| Description: |
Treatment options for non-small cell lung cancer (NSCLC) depend on disease stage and include various combinations of surgery, radiotherapy, 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. In addition, up to 40% of patients with NSCLC present with metastatic disease (Fathi, 2008). When treated with standard platinum based chemotherapy, patients with advanced NSCLC have a median survival of 8 to 11 months and a 1-year survival of 30% to 45% (Martoni, 2005; Rudd, 2005). 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
EGFR
The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (TK), is frequently overexpressed and activated in non-small-cell lung cancer (NSCLC). Drugs that inhibit EGFR signaling either prevent ligand binding to the extracellular domain (monoclonal antibodies) or inhibit intracellular TK activity (small molecule tyrosine kinase inhibitors [TKIs]). These targeted therapies dampen 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 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.
Somatic variants in the tyrosine kinase domain of the EGFR gene, notably small deletions in exon 19 and a point mutation in exon 21 (L858R, indicating substitution of leucine by arginine at codon position 858) are the most commonly found EGFR variants associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs; afatinib, erlotinib, gefitinib). These variants are referred to as sensitizing variants. Almost all patients who initially respond to an EGFR TKI experience disease progression. The most common of these secondary variants, called resistance variants, involves the substitution of methionine for threonine at position 790 (T790M) on exon20.
Fang et al reported EGFR variants (all L858R) in 3 (2%) of 146 consecutively treated Chinese patients with early-stage squamous cell carcinoma (SCC) (Fang, 2013). In a separate cohort of 63 Chinese patients with SCC who received erlotinib or gefitinib as second-or third-line treatment (63% never-smokers, 21% women), EGFR variant prevalence (all exon 19 deletion or L858R) was 23.8%.
In a comprehensive analysis of 14 studies involving 2880 patients, Mitsudomi et al reported EGFR variants in 10% of men, 7%of non-Asian patients, 7% of current or former smokers, and 2% of patients with nonadenocarcinoma histologies (Mitsudomi, 2006). Eberhard et al, observed EGFR variants in 6.4% of patients with SCC and Rosell et al, observed EGFR variants in 11.5% of patients with large cell carcinomas (Eberhard, 2005; Rosell, 2009). Both studies had small sample sizes.
In 2 other studies, the acquired EGFR T790M variant has been estimated to be present in 50% to 60% of TKI-resistant cases in approximately 200 patients (Yu, 2013; Sequist, 2011).
ALK
ALK (anaplastic large cell lymphoma kinase) is a tyrosine kinase 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
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 1% to 3% of adenocarcinomas. Unlike melanoma, about 50% of the variants in NSCLC are non-V600E variants (Thunnissen, 2014). Most BRAF variants occur more frequently in smokers.
ROS1
ROS1 codes for a receptor tyrosine kinase of the insulin receptor family, and chromosomal rearrangements result in fusion genes. The prevalence of ROS1 fusions in NSCLC varies from 0.9-3.7%. (Thunnissen, 2014). Patients with ROS1 fusions are typically never smokers with adenocarcinoma.
KRAS
The KRAS gene (which encodes 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. Variants in the KRAS gene, mainly codons 12 and 13, have been reported in 20-30% of NSCLC, and occur most often in adenocarcinomas in heavy smokers.
KRAS variants can be detected by direct sequencing, PCR technologies, or NGS.
EGFR, ALK, ROS1, and KRAS driver mutations are considered to be mutually exclusive.
HER2
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 mutations are detected mainly in exon 20 in 1-2% of NSCLC, predominantly in adenocarcinomas in nonsmoking women (Thunnissen, 2014).
RET
RET (rearranged during transfection) is a proto-oncogene that encodes a receptor tyrosine kinase growth factor. Translocations that result in fusion genes with several partners have been reported.4 RET fusions occur in 0.6-2% of NSCLCs and in 1.2-2% of adenocarcinomas (Thunnissen, 2014).
MET
MET alteration is one of the critical events for acquired resistance in EGFR-mutated adenocarcinomas refractory to EGFR-TKIs (Thunnissen, 2014).
NTRK
NTRK gene fusions encode tropomyosin receptor kinase 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 (NCCN, 2022).
PD-1/PD-L1
Programmed cell ligand-1 (PD-L1) is a transmembrane protein expressed on the surface of multiple tissue types, including many tumor cells. Blocking the PD-L1 protein may prevent cancer cells from inactivating T cells.
Tumor Mutational Burden
Tumor mutational burden, a measure of gene mutations within cancer cells, is an emerging biomarker of outcomes with immunotherapy in multiple tumor types, including lung cancer (Hellmann, 2018).
Targeted Treatment and Immunotherapy
FDA-approved targeted treatments and immunotherapies for the variants described above are summarized below. (Note this information is current as of October 17, 2022. FDA maintains a list of oncology drug approval notifications at https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications.)
EGFR
ALK
BRAF
ROS1
KRAS
HER2 (ERBB2)
RET
MET
NTRK1
PD-L1
Regulatory Status
Below is a summary of the FDA-approved targeted treatments for patients with NSCLC along with the concurrently approved companion diagnostic tests. (Note this information is current as of October 17, 2022. FDA maintains a list of cleared or approved companion diagnostics at https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.)
Treatment: Afatinib(Gilotrif)
Treatment: Alectinib (Alecensa)
Treatment: Amivantamab-vmjw (Rybrenant)
Treatment: Atezolizumab (Tecentriq)
Treatment: Brigatinib (Alunbrig)
Treatment: Capmatinib (Tabrecta)
Treatment: Cemiplimab-rwlc (Libtayo)
Treatment: Ceritinib (Zykadia)
Treatment: Crizotinib (Xalkori)
Treatment: Crizotinib (Xalkori)
Treatment: Dacomitinib (Vizimpro)
Treatment: Dabrafenib (Tafinlar) plus trametinib (Mekinist)
Treatment: Entrectinib (Rozlytrek)
Treatment: Erlotinib (Tarceva)
Treatment: Gefitinib (Iressa)
Treatment: Larotrectinib (Vitrakvi)
Treatment: Lorlatinib (Lorbrena)
Treatment: Mobocertinib (Exkivity)
Treatment: Nivolumab (Opdivo) in combination with Ipilimumab (Yervoy)
Treatment: Osimertinib (Tagrisso)
Treatment: Pembrolizumab (Keytruda)
Treatment: Pralsetinib (Gavreto)
Treatment: Selpercatinib (Retevmo)
Treatment: Sotorasib (Lumakras)
Treatment: Tepotinib (Tepmetko)
Treatment: Fam-trastuzumabderuxtecan-nxki (Enhertu)
Coding Guidelines:
Effective in 2013, there is a specific CPT code for testing for common variants of EGFR:
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)
Prior to the creation of code 81235, no specific CPT codes were available, and this laboratory test would likely have been coded using a series of nonspecific genetic testing codes. One laboratory website listed the following group of CPT codes for this testing: 83907, 83900(x2), 83901(x18), 83891, 83896(x29), 83898(x6), 88381, 83914(x29), 83912-26.
If testing is done by immunohistochemical assay, CPT code 88342 would likely be reported. If testing is done by fluorescence in situ hybridization (FISH), CPT code 88365 would likely be reported.
Testing for mutations in the other genes listed above would be reported with the unlisted molecular pathology code 81479 unless a more specific code exists such as 81275 for KRAS, 81404/81405 for RET, or 81406 for BRAF.
Testing for NSCLC to predict sensitivity to Erlotinib or KRAS mutation to predict sensitivity to Erlotinib and Cetuximab was previously included in Archived Policies 2011004 and 2010040.
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Policy/ Coverage: |
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
Effective October 2023
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
EGFR TESTING: Analysis of tumor for somatic variants in exons 18 through 21 (eg, G719X, L858R, T790M, S6781, L861Q) within the epidermal growth factor receptor (EGFR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an FDA-approved (e.g., erlotinib [Tarceva] alone or in combination with ramucirumab [Cyramza], gefitinib [Iressa], afatinib [Gilotrif], dacomitinib ]Vizimpro], osimertinib [Tagrisso]), or mobocertinib [Exkivity] in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell non-small-cell lung cancer (NSCLC), and NSCLC not otherwise specified, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of tumor tissue for somatic variants in exon 20 (eg, insertion mutations) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an FDA-approved therapy (eg, mobocertinib [Exkivity] or amivantamab [Rybrevant]) in individuals with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
At diagnosis, only analysis of plasma for somatic variants in exons 19 through 21 (eg, exon 19 deletions, L858R, T790M ) within the EGFR gene, using the cobas EGFR Mutation Test v2, Guardant360 CDx test (0242U), FoundationOne Liquid CDx, OncoBEAM test or InVisionFirst-Lung test to detect circulating tumor DNA (ctDNA), meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC not otherwise specified, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
At progression, analysis of the EGFR T790M resistance variant for targeted therapy with osimertinib using ctDNA using the cobas EGFR Mutation Test v2, Guardant360 CDx test (0242U), OncoBEAM test or InVisionFirst-Lung test to detect circulating tumor DNA (ctDNA), meets member benefit certificate primary coverage criteria in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC, not otherwise specified when tissue biopsy to obtain new tissue is not feasible, (e.g., in those who do not have enough tissue for standard molecular testing using formalin-fixed paraffin-embedded tissue, do not have a biopsy-amenable lesion, or cannot undergo biopsy) and when the individual does not have any FDA-labeled contraindications to Osimertinib and it is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic variants in exon 20 (eg, insertion mutations) within the EGFR gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy in individuals with NSCLC (eg, amivantamab [Rybrevant]), if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels
ALK TESTING: Analysis of somatic rearrangement variants of the anaplastic lymphoma kinase (ALK) gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved ALK inhibitor therapy (e.g., crizotinib [Xalkori], ceritinib [Zykadia], alectinib [Alecensa], brigatinib [Alunbrig], or lorlatinib [Lorbrena]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic rearrangement variants of the ALK gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved ALK inhibitor therapy in individuals with NSCLC (eg, alectinib [Alcensa]), if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels
BRAF V600E TESTING: Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved BRAF and/or MEK-inhibitor therapy (eg, dabrafenib [Tafinlar] and trametinib [Mekinist]), in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
ROS1 TESTING: Analysis of tumor tissue for somatic rearrangement variants of the ROS1 gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved ROS1 inhibitor therapy (e.g., crizotinib [Xalkori] or entrectinib [Rozlytrek]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
KRAS Testing: Analysis of tumor tissue for somatic variants of the KRAS gene meets member benefit certificate primary coverage criteria to predict treatment response to sotorasib (Lumakras) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic variants of the KRAS (e.g., G12C) using an FDA- approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage to predict treatment response to sotorasib (Lumakras) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
HER2 Testing: Analysis of tumor tissue for somatic alterations in the HER2(ERBB2) gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved therapy (eg, fam-trastuzumab deruxtecan-nxki [Enhertu]) in individuals with unresectable or metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic alterations in the HER2(ERBB2) gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy (eg, fam-trastuzumab deruxtecan-nxki [Enhertu]) in individuals with unresectable or metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
NTRK GENE FUSION TESTING: Analysis of tumor tissue for somatic by immunohistochemistry (IHC) of NTRK gene fusions meets member benefit certificate primary coverage criteria to predict treatment response to entrectinib (Rozlytrek) or Larotrectinib (Vitrakvi) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
RET REARRANGEMENT TESTING: Analysis of tumor tissue for somatic alterations in the RET gene meets member benefit certificate primary coverage criteria to predict treatment response to pralsetinib (Gavreto) or selpercatinib (Retevmo) in individuals with metastatic NSCLC if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
MET EXON 14 SKIPPING ALTERATION: Analysis of tumor tissue for somatic alteration that leads to MET exon 14 skipping meets member benefit certificate primary coverage criteria to predict treatment response to capmatinib (Tabrecta) in individuals with metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label to predict treatment response to capmatinib (Tabrecta). in individuals with metastatic NSCLC.
Analysis of plasma for somatic alteration that leads to MET exon 14 skipping using an FDA-approved companion diagnostic plasma test specimens to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to MET inhibitor therapy (e.g., capmatinib [Tabrecta]) in patients with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
PD-L1 TESTING: PD-L1 testing of tumor tissue meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved therapy (e.g., atezolizumab [Tecentriq], nivolumab [Opdivo] in combination with ipilimumab [Yervoy], pembrolizumab [Keytruda], or cemiplimab-rwlc [Libtayo]) in individuals with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label
Plasma Testing When Tissue is Insufficient: Plasma tests for oncogenic driver variants meeting primary coverage criteria on tissue biopsy when there is insufficient tissue meets member benefit certificate primary coverage criteria to predict treatment response to targeted therapy for individuals meeting all the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the following does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any clinical situations or other applications not addressed above or in other policies for individuals with NSCLC:
For members with contracts without primary coverage criteria, the use of the above tests for any clinical situation or application not addressed in this or other policies for individuals with NSCLC are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Augmentative algorithmic analysis of digitized whole slide imaging (e.g., LungOI, 0414U) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with NSCLC.
For members with contracts without primary coverage criteria, augmentative algorithmic analysis of digitized whole slide imaging (e.g., LungOI, 0414U) for individuals with NSCLC is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective June 2023 through September 2023
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
EGFR TESTING: Analysis of tumor for somatic variants in exons 18 through 21 (eg, G719X, L858R, T790M, S6781, L861Q) within the epidermal growth factor receptor (EGFR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an FDA-approved (e.g., erlotinib [Tarceva] alone or in combination with ramucirumab [Cyramza], gefitinib [Iressa], afatinib [Gilotrif], dacomitinib ]Vizimpro], osimertinib [Tagrisso]), or mobocertinib [Exkivity] in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell non-small-cell lung cancer (NSCLC), and NSCLC not otherwise specified, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of tumor tissue for somatic variants in exon 20 (eg, insertion mutations) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an FDA-approved therapy (eg, mobocertinib [Exkivity] or amivantamab [Rybrevant]) in individuals with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label
At diagnosis, only analysis of plasma for somatic variants in exons 19 through 21 (eg, exon 19 deletions, L858R, T790M ) within the EGFR gene, using the cobas EGFR Mutation Test v2, Guardant360 CDx test, FoundationOne Liquid CDx, OncoBEAM test or InVisionFirst-Lung test to detect circulating tumor DNA (ctDNA), meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC not otherwise specified, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
At progression, analysis of the EGFR T790M resistance variant for targeted therapy with osimertinib using ctDNA using the cobas EGFR Mutation Test v2, Guardant360 CDx test, OncoBEAM test or InVisionFirst-Lung test to detect circulating tumor DNA (ctDNA), meets member benefit certificate primary coverage criteria in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC, not otherwise specified when tissue biopsy to obtain new tissue is not feasible, (e.g., in those who do not have enough tissue for standard molecular testing using formalin-fixed paraffin-embedded tissue, do not have a biopsy-amenable lesion, or cannot undergo biopsy) and when the individual does not have any FDA-labeled contraindications to Osimertinib and it is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic variants in exon 20 (eg, insertion mutations) within the EGFR gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy in individuals with NSCLC (eg, amivantamab [Rybrevant]), if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels
ALK TESTING: Analysis of somatic rearrangement variants of the anaplastic lymphoma kinase (ALK) gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved ALK inhibitor therapy (e.g., crizotinib [Xalkori], ceritinib [Zykadia], alectinib [Alecensa], brigatinib [Alunbrig], or lorlatinib [Lorbrena]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic rearrangement variants of the ALK gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved ALK inhibitor therapy in individuals with NSCLC (eg, alectinib [Alcensa]), if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels
BRAF V600E TESTING: Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved BRAF and/or MEK-inhibitor therapy (eg, dabrafenib [Tafinlar] and trametinib [Mekinist]), in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
ROS1 TESTING: Analysis of tumor tissue for somatic rearrangement variants of the ROS1 gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved ROS1 inhibitor therapy (e.g., crizotinib [Xalkori] or entrectinib [Rozlytrek]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
KRAS Testing: Analysis of tumor tissue for somatic variants of the KRAS gene meets member benefit certificate primary coverage criteria to predict treatment response to sotorasib (Lumakras) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic variants of the KRAS (e.g., G12C) using an FDA- approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage to predict treatment response to sotorasib (Lumakras) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
HER2 Testing: Analysis of tumor tissue for somatic alterations in the HER2(ERBB2) gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved therapy (eg, fam-trastuzumab deruxtecan-nxki [Enhertu]) in individuals with unresectable or metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic alterations in the HER2(ERBB2) gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy (eg, fam-trastuzumab deruxtecan-nxki [Enhertu]) in individuals with unresectable or metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
NTRK GENE FUSION TESTING: Analysis of tumor tissue for somatic by immunohistochemistry (IHC) of NTRK gene fusions meets member benefit certificate primary coverage criteria to predict treatment response to entrectinib (Rozlytrek) or Larotrectinib (Vitrakvi) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
RET REARRANGEMENT TESTING: Analysis of tumor tissue for somatic alterations in the RET gene meets member benefit certificate primary coverage criteria to predict treatment response to pralsetinib (Gavreto) or selpercatinib (Retevmo) in individuals with metastatic NSCLC if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
MET EXON 14 SKIPPING ALTERATION: Analysis of tumor tissue for somatic alteration that leads to MET exon 14 skipping meets member benefit certificate primary coverage criteria to predict treatment response to capmatinib (Tabrecta) in individuals with metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label to predict treatment response to capmatinib (Tabrecta). in individuals with metastatic NSCLC.
Analysis of plasma for somatic alteration that leads to MET exon 14 skipping using an FDA-approved companion diagnostic plasma test specimens to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to MET inhibitor therapy (e.g., capmatinib [Tabrecta]) in patients with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
PD-L1 TESTING: PD-L1 testing of tumor tissue meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved therapy (e.g., atezolizumab [Tecentriq], nivolumab [Opdivo] in combination with ipilimumab [Yervoy], pembrolizumab [Keytruda], or cemiplimab-rwlc [Libtayo]) in individuals with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label
Plasma Testing When Tissue is Insufficient: Plasma tests for oncogenic driver variants meeting primary coverage criteria on tissue biopsy when there is insufficient tissue meets member benefit certificate primary coverage criteria to predict treatment response to targeted therapy for individuals meeting all the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the following does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any clinical situations or other applications not addressed above or in other policies for individuals with NSCLC:
For members with contracts without primary coverage criteria, the use of the above tests for any clinical situation or application not addressed in this or other policies for individuals with NSCLC are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 2022 through May 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
EGFR TESTING: Analysis of somatic variants in exons 18 through 21 (eg, G719X, L858R, T790M, S6781, L861Q) within the epidermal growth factor receptor (EGFR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an FDA-approved (e.g., erlotinib [Tarceva] alone or in combination with ramucirumab [Cyramza], gefitinib [Iressa], afatinib [Gilotrif], dacomitinib ]Vizimpro], osimertinib [Tagrisso]), or mobocertinib [Exkivity] in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell non-small-cell lung cancer (NSCLC), and NSCLC not otherwise specified, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of tumor tissue for somatic variants in exon 20 (eg, insertion mutations) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an FDA-approved therapy (eg, mobocertinib [Exkivity] or amivantamab [Rybrevant]) in individuals with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label
At diagnosis, only analysis of somatic variants in exons 19 through 21 (eg, exon 19 deletions, L858R, T790M ) within the EGFR gene, using the cobas EGFR Mutation Test v2, Guardant360 CDx test, FoundationOne Liquid CDx, OncoBEAM test or InVisionFirst-Lung test to detect circulating tumor DNA (ctDNA), meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC not otherwise specified, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
At progression, analysis of the EGFR T790M resistance variant for targeted therapy with osimertinib using ctDNA using the cobas EGFR Mutation Test v2, Guardant360 CDx test, OncoBEAM test or InVisionFirst-Lung test to detect circulating tumor DNA (ctDNA), meets member benefit certificate primary coverage criteria in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell NSCLC, and NSCLC, not otherwise specified when tissue biopsy to obtain new tissue is not feasible, (e.g., in those who do not have enough tissue for standard molecular testing using formalin-fixed paraffin-embedded tissue, do not have a biopsy-amenable lesion, or cannot undergo biopsy) and when the individual does not have any FDA-labeled contraindications to Osimertinib and it is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic variants in exon 20 (eg, insertion mutations) within the EGFR gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy in individuals with NSCLC (eg, amivantamab [Rybrevant]), if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels
ALK TESTING: Analysis of somatic rearrangement variants of the anaplastic lymphoma kinase (ALK) gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved ALK inhibitor therapy (e.g., crizotinib [Xalkori], ceritinib [Zykadia], alectinib [Alecensa], brigatinib [Alunbrig], or lorlatinib [Lorbrena]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic rearrangement variants of the ALK gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved ALK inhibitor therapy in individuals with NSCLC (eg, alectinib [Alcensa]), if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels
BRAF V600E TESTING: Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved BRAF and/or MEK-inhibitor therapy (eg, dabrafenib [Tafinlar] and trametinib [Mekinist]), in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
ROS1 TESTING: Analysis of tumor tissue for somatic rearrangement variants of the ROS1 gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved ROS1 inhibitor therapy (e.g., crizotinib [Xalkori] or entrectinib [Rozlytrek]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
KRAS Testing: Analysis of tumor tissue for somatic variants of the KRAS gene meets member benefit certificate primary coverage criteria to predict treatment response to sotorasib (Lumakras) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic variants of the KRAS (e.g., G12C) using an FDA- approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage to predict treatment response to sotorasib (Lumakras) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
HER2 Testing: Analysis of tumor tissue for somatic alterations in the HER2(ERBB2) gene meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved therapy (eg, fam-trastuzumab deruxtecan-nxki [Enhertu]) in individuals with unresectable or metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
Analysis of plasma for somatic alterations in the HER2(ERBB2) gene using an FDA-approved companion diagnostic plasma test to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to an FDA-approved therapy (eg, fam-trastuzumab deruxtecan-nxki [Enhertu]) in individuals with unresectable or metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
NTRK GENE FUSION TESTING: Analysis by immunohistochemistry (IHC) of NTRK gene fusions meets member benefit certificate primary coverage criteria to predict treatment response to entrectinib or larotrectinib in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
RET REARRANGEMENT TESTING: Analysis of tumor tissue for somatic alterations in the RET gene meets member benefit certificate primary coverage criteria to predict treatment response to pralsetinib (Gavreto) or selpercatinib (Retevmo) in individuals with metastatic NSCLC if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
MET EXON 14 SKIPPING ALTERATION: Analysis of tumor tissue for somatic alteration that leads to MET exon 14 skipping meets member benefit certificate primary coverage criteria to predict treatment response to capmatinib (Tabrecta) in individuals with metastatic NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label to predict treatment response to capmatinib (Tabrecta) in individuals with metastatic NSCLC.
Analysis of plasma for somatic alteration that leads to MET exon 14 skipping using an FDA-approved companion diagnostic plasma test specimens to detect ctDNA meets member benefit certificate primary coverage criteria as an alternative to tissue biopsy to predict treatment response to MET inhibitor therapy (e.g., capmatinib [Tabrecta]) in patients with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and both the agent and ctDNA test are intended to be used consistently with their FDA-approved labels.
PD-L1 TESTING: PD-L1 testing of tissue meets member benefit certificate primary coverage criteria to predict treatment response to an FDA-approved therapy (e.g., atezolizumab [Tecentriq], nivolumab [Opdivo] in combination with ipilimumab [Yervoy], pembrolizumab [Keytruda], or cemiplimab-rwlc [Libtayo]) in individuals with NSCLC, if the individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label
Plasma Testing When Tissue is Insufficient: Plasma tests for oncogenic driver variants meeting primary coverage criteria on tissue biopsy when there is insufficient tissue meets member benefit certificate primary coverage criteria to predict treatment response to targeted therapy for individuals meeting all the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the following does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any clinical situations or other applications not addressed above or other policies for individuals with NSCLC:
For members with contracts without primary coverage criteria, the use of the above tests for any clinical situation or application not addressed in this or other policies for individuals with NSCLC are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective October 1, 2022 through October 31, 2022
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
EGFR TESTING: Analysis of somatic variants in exons 18 through 21 (e.g., G719X, L858R, T790M, S6781, L861Q) within the epidermal growth factor receptor (EGFR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an EGFR tyrosine kinase inhibitor therapy (e.g., erlotinib [Tarceva], gefitinib [Iressa], afatinib [Gilotrif], osimertinib [Tagrisso]), or mobocertinib [Exkivity] in individuals with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell non-small-cell lung cancer, and non-small-cell lung cancer not otherwise specified.
Use of a circulating tumor DNA test (cobas® EGFR Mutation Test v2) to detect the above specific mutations of the EGFR gene meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when the volume of formalin-fixed paraffin-embedded tumor tissue (FFPET) available for testing is insufficient and the other above criteria are met.
KRAS Testing: Analysis of the KRAS gene for the presence of KRAS G12C mutation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to sotorasib (Lumakras) in individuals with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received one prior systemic treatment.
ALK TESTING: Analysis of somatic rearrangement mutations of the ALK gene meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to ALK inhibitor therapy (e.g., crizotinib, alectinib, or brigatinib in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
BRAF V600E TESTING: Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to BRAF or MEK-inhibitor therapy (e.g., dabrafenib [Tafinlar] and trametinib [Mekinist]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded, and to predict treatment response to BRAF and MEK-inhibitor combination therapy in individuals with BRAF V600E–mutated non–small cell lung cancer.
ROS1 TESTING: Analysis of somatic rearrangement variants of the ROS1 gene meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to ALK inhibitor therapy (crizotinib [Xalkori]) in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
NTRK GENE FUSION TESTING: Analysis by immunohistochemistry (IHC) of NTRK gene fusions meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to entrectinib or larotrectinib in individuals with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
RET REARRANGEMENT TESTING: Analysis of genetic alteration in the RET gene meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to pralsetinib (Gavreto) or selpercatinib (Retevmo) in individuals with metastatic NSCLC.
MET EXON 14 SKIPPING ALTERATION: Analysis of genetic alteration that leads to MET exon 14 skipping gene meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to capmatinib (Tabrecta) in individuals with metastatic NSCLC.
PD-L1 TESTING: PD-L1 testing gene meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to atezolizumab (Tecentriq), nivolumab (Opdivo) in combination with ipilimumab (Yervoy) or pembrolizumab (Keytruda) in individuals with metastatic NSCLC.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of the above tests for any clinical situation or application not addressed in this or other policies for individuals with NSCLC, including but not limited to the following, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
For members with contracts without primary coverage criteria, the use of the above tests for any clinical situation or application not addressed in this or other policies for individuals with NSCLC, including but not limited to the following, are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 2021 to September 2022
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
EGFR TESTING: Analysis of somatic variants in exons 18 through 21 (eg, G719X, L858R, T790M, S6781, L861Q) within the epidermal growth factor receptor (EGFR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an EGFR tyrosine kinase inhibitor therapy (eg, erlotinib [Tarceva], gefitinib [Iressa], afatinib [Gilotrif], osimertinib [Tagrisso]), or mobocertinib [Exkivity] in patients with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell non-small-cell lung cancer, and non-small-cell lung cancer not otherwise specified.
Use of a circulating tumor DNA test (cobas® EGFR Mutation Test v2 ) to detect the above specific mutations of the EGFR gene meets primary coverage criteria when the volume of formalin-fixed paraffin-embedded tumor tissue (FFPET) available for testing is insufficient and the other above criteria are met.
KRAS Testing: Analysis of the KRAS gene for the presence of KRAS G12C mutation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes to predict treatment response to sotorasib (Lumakras) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received one prior systemic treatment.
ALK TESTING: Analysis of somatic rearrangement mutations of the ALK gene meets member benefit certificate primary coverage criteria to predict treatment response to ALK inhibitor therapy (eg, crizotinib, alectinib, or brigatinib in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
BRAF V600E TESTING: Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to BRAF or MEK-inhibitor therapy (eg, dabrafenib [Tafinlar] and trametinib [Mekinist]), in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
ROS1 TESTING: Analysis of somatic rearrangement variants of the ROS1 gene meets member benefit certificate primary coverage criteria to predict treatment response to ALK inhibitor therapy (crizotinib [Xalkori]) in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
NTRK GENE FUSION TESTING: Analysis by immunohistochemistry (IHC) of NTRK gene fusions meets member benefit certificate primary coverage criteria to predict treatment response to entrectinib or larotrectinib in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
RET REARRANGEMENT TESTING: Analysis of genetic alteration in the RET gene meets member benefit certificate primary coverage criteria to predict treatment response to pralsetinib (Gavreto) or selpercatinib (Retevmo) in patients with metastatic NSCLC.
MET EXON 14 SKIPPING ALTERATION: Analysis of genetic alteration that leads to MET exon 14 skipping gene meets member benefit certificate primary coverage criteria to predict treatment response to capmatinib (Tabrecta) in patients with metastatic NSCLC.
PD-L1 TESTING: PD-L1 testing gene meets member benefit certificate primary coverage criteria to predict treatment response to atezolizumab (Tecentriq), nivolumab (Opdivo) in combination with ipilimumab (Yervoy) or pembrolizumab (Keytruda) in patients with metastatic NSCLC.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the following indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any clinical situations or other applications not described above for NSCLC:
For members with contracts without primary coverage criteria testing for the following indications are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage in any clinical situations or other applications not described above for NSCLC:
Effective July 2021 to October 2021
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this or another specific policy are met, limited genetic cancer susceptibility panels are covered, including only the gene variants for which a given member qualifies, as outlined in the policy.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
EGFR TESTING: Analysis of somatic variants in exons 18 through 21 (eg, G719X, L858R, T790M, S6781, L861Q) within the epidermal growth factor receptor (EGFR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to an EGFR tyrosine kinase inhibitor therapy (eg, erlotinib [Tarceva], gefitinib [Iressa], afatinib [Gilotrif], or osimertinib [Tagrisso]) in patients with advanced lung adenocarcinoma, large cell carcinoma, advanced squamous cell non-small-cell lung cancer, and non-small-cell lung cancer not otherwise specified.
Use of a circulating tumor DNA test (cobas® EGFR Mutation Test v2 ) to detect the above specific mutations of the EGFR gene meets primary coverage criteria when the volume of formalin-fixed paraffin-embedded tumor tissue (FFPET) available for testing is insufficient and the other above criteria are met.
KRAS Testing: Analysis of the KRAS gene for the presence of KRAS G12C mutation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes to predict treatment response to sotorasib (Lumakras) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received one prior systemic treatment.
ALK TESTING: Analysis of somatic rearrangement mutations of the ALK gene meets member benefit certificate primary coverage criteria to predict treatment response to ALK inhibitor therapy (eg, crizotinib, alectinib, or brigatinib in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
BRAF V600E TESTING: Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to BRAF or MEK-inhibitor therapy (eg, dabrafenib [Tafinlar] and trametinib [Mekinist]), in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
ROS1 TESTING: Analysis of somatic rearrangement variants of the ROS1 gene meets member benefit certificate primary coverage criteria to predict treatment response to ALK inhibitor therapy (crizotinib [Xalkori]) in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
NTRK GENE FUSION TESTING: Analysis by immunohistochemistry (IHC) of NTRK gene fusions meets member benefit certificate primary coverage criteria to predict treatment response to entrectinib or larotrectinib in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded.
RET REARRANGEMENT TESTING: Analysis of genetic alteration in the RET gene meets member benefit certificate primary coverage criteria to predict treatment response to pralsetinib (Gavreto) or selpercatinib (Retevmo) in patients with metastatic NSCLC.
MET EXON 14 SKIPPING ALTERATION: Analysis of genetic alteration that leads to MET exon 14 skipping gene meets member benefit certificate primary coverage criteria to predict treatment response to capmatinib (Tabrecta) in patients with metastatic NSCLC.
PD-L1 TESTING: PD-L1 testing gene meets member benefit certificate primary coverage criteria to predict treatment response to atezolizumab (Tecentriq), nivolumab (Opdivo) in combination with ipilimumab (Yervoy) or pembrolizumab (Keytruda) in patients with metastatic NSCLC.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the following indications does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any clinical situations or other applications not described above for NSCLC:
For members with contracts without primary coverage criteria testing for the following indications are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage in any clinical situations or other applications not described above for NSCLC:
Due to the length of the policy, criteria for dates of service prior to October 2021, are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”
The most recent literature search conducted for EGFR mutation testing was through December 2013, for KRAS mutation testing through January 2014, and for all remaining mutations addressed in this policy through September 4, 2014.
EGFR
Two publications (Lynch, 2004; Paez, 2004) demonstrated that the underlying molecular mechanism underpinning dramatic responses in these favorably prognostic groups appeared to be the presence of activating somatic mutations in the TK domain of the EGFR gene, notably small deletions in exon 19 and a point mutation in exon 21 (L858R, indicating substitution of leucine by arginine at codon position 858). These can be detected by direct sequencing or PCR technologies.
A TEC Assessment on this topic was first published in November 2007. The Assessment concluded that there was insufficient evidence to permit conclusions about the clinical validity or utility of EGFR mutation testing to predict erlotinib sensitivity or to guide treatment in patients with NSCLC. This Assessment was updated in 2010, with revised conclusions indicating that EGFR mutation testing has clinical utility in selecting or deselecting patients for treatment with erlotinib.
A 2013 meta-analysis (Lee, 2013) of 23 trials of erlotinib, gefitinib, and afatinib in patients with advanced NSCLC reported improved progression free survival (PFS) in EGFR mutation-positive patients treated with EGFR TKIs in the first- and second-line settings and for maintenance therapy. (Comparisons were with chemotherapy, chemotherapy and placebo, and placebo in the first-line, second-line, and maintenance therapy settings, respectively.) Among EGFR mutation-negative patients, PFS was improved with EGFR TKIs compared with placebo maintenance but not in the first- and second-line settings. Overall survival (OS) did not differ between treatment groups in either mutation-positive or mutation-negative patients.
Statistical heterogeneity was not reported for any outcome. The authors concluded that EGFR mutation testing is indicated to guide treatment selection in NSCLC patients.
Erlotinib
Thirteen publications provide data on EGFR mutations in tumor samples obtained from NSCLC patients in erlotinib treatment studies. Nine of these (Ahn, 2008; Amann, 2010; Felip, 2008; Miller, 2008; chneider, 2008; Eberhard, 2005; Giaccone, 2006; Jackson, 2007; Zhu, 2008) were nonconcurrent-prospective studies of treatment naïve and previously-treated patients who received erlotinib and were then tested for the presence or absence of mutations; 4 (see Table 1) were prospective 1-arm enrichment studies of mutation-positive or wild-type patients treated with erlotinib. In 3 studies of EGFR mutation-positive patients (Jackman. 2009; Rosell, 2009; Sun, 2011) objective radiologic response was 40% to 70%, median PFS was 8 to 14 months, and median OS was 16 to 29 months. In patients with wild-type tumors (Yoshioka, 2010) objective radiologic response was 3.3%, PFS was 2.1 months, and overall survival (OS) was 9.2 months.
Clinical Response in Prospective Studies of Erlotinib Therapy in Patients with EGFR
Gene Mutation-Positive Advanced NSCLCa
Abbreviation explanations for information below:
CI: confidence interval; OS: overall survival; PFS: progression-free survival.
a All patients had stage IIIA/IV NSCLC.
EGFR mutation positive
EGFR mutation negative (wild type)
In 2011, Zhou et al reported the results of a phase 3 prospective clinical trial of first-line treatment of
Chinese patients with EGFR mutation (exon 19 deletion or L858R)-positive NSCLC (87% adenocarcinoma) randomized to treatment with erlotinib (n=83) or standard chemotherapy (gemcitabine plus carboplatin, n=82) (Zhou, 2011). PFS was significantly longer in patients who received erlotinib (13.1 vs 4.5 months; hazard ratio [HR], 0.16; p<0.001). Patients treated with erlotinib experienced fewer grade 3 and 4 toxic effects and more clinically relevant improvements in quality of life (Chen, 2013) than those who received chemotherapy. These results were duplicated in a European population in the 2012 EURTAC trial (NCT00446225), a multicenter, open-label, randomized Phase 3 trial (Rosell, 2012). Adult patients with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with NSCLC were randomized. Eighty-six received erlotinib, and 87 received standard chemotherapy. A planned interim analysis showed that the primary end point had been met. At the time the study was halted (Jan 26, 2011), median PFS was 9.7 months (95% confidence interval [CI], 8.4 to 12.3) vs 5.2 months (95% CI, 4.5 to 5.8) in the erlotinib and standard chemotherapy groups, respectively (HR=0.37; 95% CI, 0.25 to 0.54; p<0.001). Six percent of patients receiving erlotinib had treatment-related severe adverse events compared with 20% of those receiving a standard chemotherapy regimen.
In 2011, Petrelli et al (Petrelli, 2012) reported a meta-analysis of 13 randomized trials of 1260 patients with EGFR mutated NSCLC who received TKIs for first-line, second-line, or maintenance therapy, and compared outcomes with standard therapy. Overall, they noted that in patients, use of EGFR TKIs increased the chance of obtaining an objective response almost 2-fold when compared with chemotherapy. Response rates were 70% vs 33% in first-line trials and 47% vs 28.5% in second-line trials. Tyrosine kinase inhibitors reduced the hazard of progression by 70% in all trials and by 65% in first-line trials; however, they did not improve overall survival.
In a 2010 pooled analysis of patients with EGFR mutations (most commonly exon 19 deletions and
L858R substitution mutations in exon 21), median PFS was 13.2 months in patients treated with erlotinib and 5.9 months in patients treated with standard chemotherapy (p<0.001) (Paz-Ares, 2010). Patients with EGFR mutations appear to be ideal candidates for treatment with erlotinib. Identification of patients likely to respond or fail to respond to erlotinib leads to tailored choices of treatment likely to result in predictable and desirable outcomes.
Nine other studies totaling 630 patients have compared outcomes in EGFR mutation-positive and EGFR wild-type patients who were treated with erlotinib (see Table 2).
Outcomes in Patients According to EGFR Mutation Status in Response to Treatment With
Erlotinib (9 studies of 630 patients)
Abbreviation explanations for information below:
OS: overall survival; PFS: progression-free survival.
In a 2013 randomized controlled trial (RCT), Garassino et al in Italy compared the efficacy of erlotinib and docetaxel as second-line therapy in 219 EGFR wild-type patients with metastatic NSCLC who had received previous platinum-based therapy (Garassino, 2013). Most patients (69%) had adenocarcinoma; 25% had squamous cell carcinoma (SCC). With a median follow-up of 33 months, median PFS was 2.9 months with docetaxel and 2.4 months with erlotinib (adjusted HR=0.71; 95% CI, 0.53 to 0.95; p=0.02). Median overall survival was 8.2 months with docetaxel and 5.4 months with erlotinib (adjusted HR=0.73; 95% CI, 0.53 to 1.00; p=0.05). Grade 3 or higher skin adverse events occurred in 14% of the erlotinib group and did not occur in the docetaxel group. Grade 3 or higher neutropenia occurred only in the docetaxel group (20%). As stated in an accompanying editorial, “[T]he efficacy of EGFR tyrosine kinase inhibitors is very limited for second-line treatment of wild-type EGFR NSCLC” (Jassem, 2013). A 2013 meta-analysis of 3 trials in patients with wild-type EGFR reported improved overall survival with erlotinib treatment in second and third line and maintenance settings (Jazieh, 2013). However, 75% of patients in the control arms in this analysis received placebo.
EGFR mutations may provide prognostic information (about disease recurrence and survival), as well as predictive information (about treatment response). In a 2005 study by Eberhard et al, improved outcomes were observed for EGFR mutation-positive patients compared with wild-type patients regardless of treatment (standard chemotherapy or standard chemotherapy plus erlotinib). Objective radiologic response was 38% versus 23% (p=0.01), median time to progression was 8 months versus 5 months (p<0.001), and median OS was not reached versus 10 months (p<0.001).
Afatinib
Unlike erlotinib (and gefitinib) that selectively inhibit EGFR, afatinib inhibits not only EGFR but also human epidermal growth factor receptor 2 (HER2) and HER4 and may have activity in patients with acquired resistance to TKIs (who often harbor a T790M mutation [substitution of threonine by methionine at codon 790] in EGFR exon 20). The efficacy and safety of afatinib was evaluated in the LUX-Lung series of studies.
LUX-Lung 3 was an RCT in 345 patients with stage IIIB or IV, EGFR mutation-positive, lung adenocarcinoma who were previously untreated for advanced disease (Sequist, 2013). Seventy-two percent of patients were Asian, 26% were white, and 90% (308 patients) had common EGFR mutations (exon 19 deletion or L858R substitution mutation in exon 21). Patients received either afatinib or chemotherapy (cisplatin plus pemetrexed). In stratified analysis of patients with common EGFR mutations, median PFS was 13.6 months for the afatinib group and 6.9 months for the chemotherapy group (HR=0.47; 95% CI, 0.34 to 0.65; p=0.001). Median PFS for the 10% of patients who had other EGFR mutations was not reported, but median PFS for the entire patient sample was 11.1 months in the afatinib group and 6.9 months in the chemotherapy group (HR=0.58; 95% CI, 0.43 to 0.78; p=0.001). Incidence of objective response in the entire patient sample was 56% in the afatinib group and 23% in the chemotherapy group (p=0.001). With a median follow-up of 16.4 months, median OS was not reached in any group; preliminary analysis indicated no difference in OS between the 2 treatment groups in the entire patient sample (HR=1.12; 95% CI, 0.73 to 1.73; p=0.60). Patients in the afatinib group reported greater improvements in dyspnea, cough, and global health status/quality of life than those in the chemotherapy group (Yang, 2013). Grade 3 or higher diarrhea, rash, and paronychia (nail infection) occurred in 14%, 16%, and 11% of afatinib-treated patients respectively, and in no patients in the chemotherapy group. Grade 3 or higher mucositis (primarily stomatitis) occurred in 9% of the afatinib group and 0.9% of the chemotherapy group (Sequist, 2013).
Three other published LUX-Lung studies evaluated patients with stage IIIB or IV lung adenocarcinomas who were previously treated for advanced disease, but each had design flaws that limit the interpretation of results.
EGFR Mutation Frequency
In 2009, Rosell et al reported EGFR mutations in 16.6% of the overall patient sample but noted an increased prevalence in women (69.7%), patients who never smoked (66.6%), and patients with adenocarcinomas (80.9%). Based on these findings, Rosell et al recommended EGFR mutation screening in women with lung cancer with nonsquamous cell tumors who have never smoked. Other reports on the mutation frequencies have found higher prevalences among East Asians when compared with other ethnicities (38% vs 15%, respectively) (Rosell, 2009). Although there is a greater proportion of EGFR mutations in these special populations (women, never smokers, patients with adenocarcinoma, and/or Asians), many patients without these selected demographics still exhibit EGFR mutations and would benefit from erlotinib treatment.
In a comprehensive analysis of 14 studies involving 2880 patients, Mitsudomi et al (Mitsudomi, 2006), reported EGFR mutations in 10% of men, 7% of non-Asian patients, 7% of current or former smokers, and 2% of patients with nonadenocarcinoma histologies. Although histology appeared to be the strongest discriminator, results varied across studies; for example, Eberhard et al (Eberhard, 2005) observed EGFR mutations in 6.4% of patients with squamous cell carcinomas (SCCs) and Rosell et al (Rosell, 2009) in 11.5% of patients with large cell carcinomas. (Both of these studies had small sample sizes.)
For patients with SCC, current guidelines from the National Comprehensive Cancer Network (NCCN) indicate that the low incidence of EGFR mutations in SCC “does not justify routine testing of all tumor specimens.” This conclusion is based on the Sanger Institute’s Catalogue of Somatic Mutations in Cancer
(COSMIC) (Forbes, 2012), that reported an observed EGFR mutation incidence of 2.7% in patients with SCC with an upper confidence limit for the true incidence of 3.6%. NCCN guidelines recommend consideration of mutation testing in never smokers with SCC or when biopsy specimens are small and histology is mixed. This recommendation was based on a case series of 13 patients with squamous or pseudosquamous histology (Paik, 2012). However, 7 patients (54%) were subsequently determined to have adenocarcinoma histology. All 6 remaining patients were never smokers, and all 6 had an exon 19 deletion or L858R substitution mutation in EGFR.
In 2013, the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology published joint evidence-based guidelines for molecular testing to select EGFR TKI therapy in patients with lung cancer (Lindeman, 2013). An EGFR mutation incidence of 0% to 5% in patients with SCC was reported. Recommendations for EGFR mutation testing in patients with SCC depend on tumor sample availability:
Two studies may support the potential value of EGFR mutation testing in patients with SCC, particularly in Asian populations. However, similar studies have not been reported in non-Asian populations or in populations treated with erlotinib. A 2009 study by Park et al (Park, 2009) of preselected Korean patients treated with gefitinib reported EGFR mutations in 3 of 20 male smokers with SCC (15%), a patient subgroup expected to have a low prevalence of EGFR mutations based on demographics. Clinical response was observed in 2 of 3 mutation-positive patients and 1 of 17 wild-type patients; median PFS was 5.8 months in patients with mutated EGFR and 2.4 months in the wild-type group (p=0.07). In vivo analyses by Dobashi et al (Dobashi, 2011) showed that in Japanese patients with both adenocarcinomas and SCCs, EGFR mutations were associated with downstream phosphorylation of EGFR and constitutive activation of the EGFR pathway.
In contrast, Fang et al (2013) reported EGFR mutations (all L858R) in 2% (3 patients) of 146 consecutively treated Chinese patients with early stage SCC (Park, 2009) In a separate cohort of 63 Chinese patients with SCC who received erlotinib or gefitinib as second- or third-line treatment (63% never smokers, 21% women), EGFR mutation prevalence (all exon 19 deletion or L858R) was 23.8%. Objective response occurred in 26.7% of 15 EGFR mutation-positive and 2.1% of 48 mutation-negative patients (p=0.002). Median PFS was 3.9 months and 1.9 months, respectively (p=0.19). Based on these findings, the authors concluded that routine EGFR mutation testing of all SCC specimens is not justified.
EGFR Mutation Testing
Gene sequencing is generally considered an analytic gold standard. In 2010, the Canadian Agency for
Drugs and Technologies in Health published a rapid response report on EGFR mutation analysis. Based on 11 observational studies, the report authors concluded that PCR-based approaches identify EGFR mutations with a sensitivity equivalent to that of direct sequencing.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in September 2014 found several phase 3 trials in patients with NSCLC and
EGFR mutations, assessing several different TKIs and clinical scenarios, including a TKI versus chemotherapy, a TKI +/- chemotherapy, use of TKIs in 1st versus subsequent lines of therapy and use of TKIs in the neoadjuvant setting.
Several randomized controlled trials, nonconcurrent prospective studies, and single-arm enrichment studies demonstrate that detection of epidermal growth factor receptor (EGFR) gene mutations identifies patients with non-small-cell lung cancer (NSCLC) who are likely to benefit from erlotinib or afatinib therapy and who are therefore ideal candidates for treatment with these drugs. These observations have been made in populations of patients with primarily adenocarcinomas. Currently, there is no little evidence to indicate that EGFR mutation testing can guide treatment selection in patients with squamous cell histology.
Patients who are found to have wild-type tumors are unlikely to respond to erlotinib or afatinib. These patients should be considered candidates for alternative therapies.
EGFR mutational analysis may be considered medically necessary to predict treatment response to erlotinib or afatinib in patients with advanced NSCLC; however, EGFR mutational analysis is investigational in patients with NSCLC of squamous cell type.
KRAS
KRAS and EGFR Tyrosine Kinase Inhibitors
Data on the role of KRAS mutations in non-small-cell lung cancer (NSCLC) and response to erlotinib are available from post hoc analyses of 2 phase 3 trials of TKIs in patients with wild-type (nonmutated) versus KRAS-mutated lung tumors; phase 2 trials; a large prospective study; retrospective single-arm studies; and 2 meta-analyses.
Pao et al (2005) were the first to suggest that patients with KRAS-mutated lung tumors were nonresponsive to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
(TKIs) (Pao, 2005). Thirty-six patients with bronchioloalveolar carcinoma underwent KRAS mutation analysis; 9 (25%) were found to harbor KRAS mutations. Response was by a single radiologist, who was blinded to patient outcome, using RECIST (Response Evaluation Criteria in Solid Tumors). None of 9 patients with KRAS-mutated tumors responded to erlotinib (p=0.553).
Zhu et al (2008) performed a post hoc subgroup analysis of KRAS mutations in patients with advanced
NSCLC who had failed standard chemotherapy and had been previously randomized to receive erlotinib or placebo. The original phase 3 trial (National Cancer Institute of Canada Clinical Trials Group Study
BR.21; 2005) was the first to demonstrate a significant survival advantage with the use of an EGFR TKI in previously treated NSCLC patients (Shepherd, 2005). In post hoc analysis, 206 (28%) of the original 731 tumors were tested for KRAS mutations, which were identified in 30 patients (15%). Among the 206 tested patients, 118 (57%) were assessable for response to erlotinib. Of 98 patients with wild-type KRAS, 10 (10.2%) responded to erlotinib; of 20 patients with mutated KRAS, 1 patient (5.0%) responded (hazard ratio [HR] [erlotinib vs placebo] in patients with mutated KRAS, 1.67; 95% confidence interval [CI], 0.62 to 4.50;
p=0.31]; HR in wild-type patients, 0.69; 95% CI, 0.49 to 0.97; p=0.03). In Cox regression, the interaction between KRAS mutation status and treatment was not statistically significant (p=0.09).
Eberhard et al (2005) performed a post hoc subgroup analysis of KRAS mutations in previously untreated patients with advanced NSCLC who had been randomly assigned to receive chemotherapy with or without erlotinib (Eberhard, 2005). The original phase 3 trial (TRIBUTE; 2005) randomly assigned patients to carboplatin plus paclitaxel either with or without erlotinib (Herbst, 2005). Of the original 1079 patients, tumor DNA from 274 patients (25%) was sequenced for KRAS mutations. Baseline demographics between patients with available tumor DNA and those without were balanced. KRAS mutations were detected in 55 of 274 patients (21%). Response rate for patients with wild-type KRAS was 26%, regardless of treatment received. In patients with KRAS-mutated tumors, response rate was 8% for those receiving chemotherapy with erlotinib and 23% for those receiving chemotherapy alone (p=0.16; 95% CI for difference: -5% to 35%); median overall survival (OS) was 4.4 months (95% CI, 3.4 to 12.9) in patients who received erlotinib and 13.5 months (95% CI, 11.1 to 15.9) in those who received chemotherapy alone (p=0.019).
In a 2007 a phase 2, multicenter, open-label study, Jackman et al evaluated treatment response to erlotinib in chemotherapy-naive patients 70 years of age or older who had advanced NSCLC (Jackman, 2007). Of 80 patients eligible for treatment, 41 (51%) had KRAS mutation analysis; 6 patients (15%) were mutation-positive, none of whom responded to erlotinib. Five (14%) of 35 patients with wild-type KRAS had a partial response.
In a 2008 phase 2 trial, Miller et al assessed response to erlotinib in 101 patients with lung bronchioloalveolar carcinoma (n=12) or adenocarcinoma, bronchioloalveolar subtype (n=89), according to
KRAS mutational status (Miller, 2008). Eighteen patients (18%) had KRAS-mutated tumors, and none of them responded to erlotinib (95% CI, 0%-19%; p<0.01). In patients without a KRAS mutation, response rate was 32%. Median OS in patients with KRAS-mutated tumor was 13 months versus 21 months in patients with KRAS wild-type tumor (p=0.30).
In a 2006 phase 2 trial, Giaccone et al studied response to erlotinib in 53 chemotherapy-naive patients with advanced NSCLC (Giaccone, 2006). Histologic material was available to assess KRAS mutational status from 29 patients, 10 of whom (34%) had mutations. All 10 were nonresponders to erlotinib (p=0.125).
In 2009, Boldrini et al reported on the association between KRAS and EGFR mutation status and several clinical variables in 411 patients with lung adenocarcinoma, and presented a subgroup analysis of tumor response in patients treated with erlotinib or gefitinib (Boldrini, 2009). KRAS mutations were observed in 17.9% of all patients. The subset analysis comprised 21 women with stage IV disease who received a TKI as second or third-line therapy and were assessed for radiographic tumor response using RECIST. Mean age of this subpopulation at the time of diagnosis was 60.8 years (range 40-86). Nineteen (90%) of 21 women were KRAS wild-type, and of those, 8 (42%) showed partial response, 4 (21%) had stable disease, and 7 (37%) had progressive disease. Two patients with KRAS mutations had progressive disease.
Schneider et al (2008) reported on the relationship between clinical benefit and putative tumor markers in a subgroup of patients participating in a global open-label, single-arm study of erlotinib in advanced
NSCLC, involving 7043 patients in 52 countries (the TRUST study) (Schneider, 2008). The subgroup in this publication was from German centers and comprised 311 patients with stage IIIB/IV disease who were 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 had a response to erlotinib; 2 patients had stable disease. The impact of KRAS mutation status on OS (p=0.06) and progression-free survival (PFS; p not reported) was of borderline statistical significance. The authors concluded that current data did not support selection of patients for treatment with erlotinib on the basis of tumor molecular characteristics and that further studies were needed to determine definitively whether patients with KRAS mutations can derive survival benefit from erlotinib.
Two meta-analyses on the relationship between KRAS mutations and response to EGFR TKI therapy 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 et al (2008) performed a meta-analysis of 17 studies with 1008 patients, 165 (16.4%) of whom had a KRAS mutation (Linardou, 2008). Eligible studies reported response (complete or partial) stratified by KRAS mutational status. Primary end points were sensitivity and specificity of KRAS testing, defined as KRAS mutation carriers showing no response to erlotinib (stable disease or progressive disease) and KRAS wild-type patients showing a response, respectively. Sensitivity and specificity were assessed overall and in subgroups defined by TKI received (gefitinib and/or erlotinib), response criteria (RECIST or World Health Organization), possible selection bias, and previous chemotherapy, if any. There was no significant difference in sensitivity or specificity across subgroups. The presence of a KRAS mutation was associated with a lack of response to TKIs (sensitivity: 0.21; 95% CI, 0.16 to 0.28; specificity: 0.94; 95%\ CI, 0.89 to0.97; 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 concluded that KRAS mutations conferred a high level of resistance to anti-EGFR therapies; however, this conclusion is tentative due to limitations of the study, such as lack of individual patient data. Prospective validation is needed. Furthermore, incomplete reporting of survival data precluded meaningful assessment of the effect of KRAS mutation on survival. Other limitations included heterogeneity of response end points, treatment regimens, and patient selection criteria, and the retrospective design of included studies.
Mao et al (2010) performed a meta-analysis of 22 studies in 1470 patients with NSCLC (1335 [91%] evaluable for response), 231 (17%) of whom had KRAS mutations (Mao, 2010). Studies were heterogeneous in patient populations (smoking history, tumor histology, stage, ethnicity, and treatment received) and response criteria. The primary end point was objective response rate, defined as the sum of complete and partial response. Objective response rates for patients with mutated KRAS and wild-type KRAS were 3% and 26%, respectively. Incomplete reporting of survival data precluded meaningful assessment of th 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. Median PFS in KRAS-mutated and wild-type patients was 3.0 months and 3.9 months, respectively. Median OS in KRAS-mutated and wild-type patients was 4.7 months and 10.7 months, respectively. However, only 2 studies presented hazard ratios with 95% confidence intervals for PFS and OS, and therefore, pooled analysis to derive an overall HR was not performed.
Guan et al (2013) reported on 1935 consecutive patients with NSCLC who were treated at a single institution in China (Guan, 2013) Patients with mutated KRAS were random matched on tumor, node, metastasis (TNM) stage, time of first visit within 1 year, and histology, to both EGFR mutation-positive and KRAS/EGFR wild-type patients. Seventy patients (4%) received EGFR TKI therapy. In this group, median PFS was 11.8 and 2.0 months in patients with EGFR and KRAS mutations, respectively, and 1.9 months in wild-type patients; in comparison with wild-type patients, PFS was statistically longer in patients with EGFR mutations (p<0.001) but no different in patients with KRAS mutations (p=0.48). The authors observed that “the presence of an EGFR mutation, but not a KRAS mutation, was predictive of responsiveness to EGFR TKI treatment.”
Fiala et al (2013) reported on a retrospective analysis of patients with squamous cell NSCLC who underwent EGFR, KRAS, and PIK3CA (phosphatidylinositide-3-kinase catalytic subunit-alpha) mutation testing (Fiala, 2013). Of 215 patients tested, 16 (7.4%) had mutated KRAS. Of 174 tested patients who were treated with an EGFR TKI (erlotinib or gefitinib), median PFS in 14 KRAS-mutated patients was 1.3 months versus 2.0 months in KRAS wild-type patients (n=160 [92%]); the difference was not statistically significant (Kaplan-Meier [KM] log-rank test, p=0.120). Median OS in this treated group was 5.7 months in
KRAS-mutated patients versus 8.2 months in KRAS wild-type patients, a statistically significant difference
(KM log-rank test, p=0.039). The authors concluded that KRAS mutation status may have a negative prognostic role but a predictive role was not confirmed. “Patients with squamous cell NSCLC harboring these mutations could benefit from targeted treatment and should not be excluded from treatment with EGFR TKIs.”
Two reviews published in 2013 concluded that, in comparison with KRAS mutation testing, EGFR mutation status is the preferred predictive marker for response to EGFR TKIs in patients with NSCLC.59,60
.KRAS and Anti-EGFR Monoclonal Antibodies
Two phase 3 trials, BMS-099 and FLEX, investigated platinum-based chemotherapy with and without cetuximab in the first-line setting for advanced NSCLC. Subsequently, investigations of KRAS mutation status and cetuximab treatment were performed for both trials.
In the multicenter phase 3 BMS099 trial (2010), 676 chemotherapy-naive patients with stage IIIB/IV
NSCLC were assigned to taxane and carboplatin with or without cetuximab (Lynch, 2010). The primary end point was
PFS; secondary end points were 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, this was not statistically significant. A post hoc correlative analysis of this trial was conducted to identify molecular markers for the selection of patients most likely to benefit from cetuximab (Khambata-Ford, 2010). Of the original 676 enrolled patients, 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 to 1.30; p=0.68; median survival, 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=0.91; 95% CI, 0.45 to 2.07; p=0.93; median survival, 16.8 and 10.8 months, respectively). Overall, the study showed no significant treatment-specific interactions between the presence of KRAS mutations and outcomes evaluated; treatment differences favoring the addition of cetuximab in the KRAS-mutated subgroup were consistent with those observed in the wild-type KRAS subgroup and in the overall study population. The authors concluded that the results do not support an association between KRAS mutation and lack of cetuximab benefit similar to that observed in patients with KRAS-mutated metastatic colorectal cancer. However, results should be interpreted with caution due to small subgroup sample sizes and retrospective nature of the analysis.
In the open-label, randomized, phase 3 FLEX trial, 1125 chemotherapy-naive patients with stage III/IV,
NSCLC were randomly assigned to receive either chemotherapy (cisplatin and vinorelbine) plus cetuximab (n=557) or chemotherapy alone (n=568) (Pirker, 2009P). The primary end point was OS. Patients who received chemotherapy plus cetuximab survived longer than those who received chemotherapy only (median OS, 11.3 months vs 10.1 months, respectively; HR for death, 0.87; 95% CI, 0.76 to 1.00;
p=0.04). Subsequently, KRAS mutation testing was performed on archival tumor tissue of 395 (35%) of 1125 patients (O’Byrne, 2011). KRAS mutations were detected in 75 tumors (19%). Among patients with mutated KRAS, OS in the cetuximab-containing (n=38) and chemotherapy-alone arms (n=37) was similar (median OS, 8.9 months vs 11.1 months, respectively; HR=1.00; 95% CI, 0.60 to 1.66; p=1.0). Among patients with wild-type KRAS, OS in the cetuximab-containing (n=161) and chemotherapy-alone arms (n=159) was similar (median OS, 11.4 months vs 10.3 months, respectively; HR=0.96; 95% CI, 0.75 to 1.23; p=0.74). PFS also was similar in cetuximab-containing and chemotherapy-alone arms in patients with mutated (HR=0.97; 95% CI, 0.76 to 1.24) and wild-type (HR=0.84; 95% CI, 0.50 to 1.40) KRAS. Response rates in the cetuximab-containing arm in patients with KRAS-mutated and wild-type tumors were 36.8% and 37.3%, respectively (p=0.96). Overall, there was no indication that KRAS mutation status was predictive of cetuximab effect in NSCLC.
Ongoing and Unpublished Clinical Trials
A phase 3 trial is currently recruiting patients to assess progression-free survival and secondarily OS with
dacomitinib, another selective tyrosine kinase inhibitor, compared with erlotinib for the treatment of advanced NSCLC in patients who have received one or more prior anti-cancer therapies. (NCT01360554)
KRAS mutation status will be collected at baseline. Estimated enrollment is 800, with an estimated study completion date of September 2014.
Section summary
KRAS and EGFR Tyrosine Kinase Inhibitors
Data on the role of KRAS mutations in NSCLC and response to erlotinib are available from post hoc analysis of 2 phase 3 trials that compared TKI efficacy in patients with wild-type (nonmutated) versus
KRAS-mutated lung tumors; phase 2 trials; a large prospective study; retrospective single-arm studies; and 2 meta-analyses. Although studies have shown that KRAS mutations in patients with NSCLC confer a high level of resistance to TKIs, data are insufficient to assess any association between KRAS mutation status and survival in these patients.
KRAS and Anti-EGFR Monoclonal Antibodies
A lack of response to EGFR monoclonal antibodies has been established in metastatic colorectal cancer, and use of these drugs is largely restricted to patients with wild-type KRAS. The expectation that KRAS mutation status also would be an important predictive marker for cetuximab response in NSCLC has not been shown. In 2 randomized trials with post hoc analyses of KRAS mutation status and use of cetuximab with chemotherapy, KRAS mutations did not identify patients who would not benefit from anti-
EGFR antibodies, as outcomes with cetuximab were similar regardless of KRAS mutation status.
ROS
Bergethon and colleagues conducted a retrospective analysis of the clinical characteristics and treatment outcomes of patients with NSCLC with a ROS1 rearrangement (Bergethon, 2012). The authors screened 1,073 patients from multiple institutions for ROS1 rearrangements using a FISH assay and correlated ROS1 status with clinical characteristics, overall survival, and when available, ALK rearrangement status. Clinical data were extracted from medical record review. In vitro studies with human NSCLC cell lines were also conducted to assess the responsiveness of cells with ROS1 rearrangements to crizotinib. Of the tumors that were screened, 18 (1.7%) had ROS1 rearrangements, and 31 (2.9%) had ALK rearrangements. All of the ROS1-positive tumors were adenocarcinomas. The patients with ROS1 rearrangements were significantly younger (median age 49.8 years) and more likely to be never-smokers, when compared to the ROS1-negative group (each p<.001). There was no survival difference observed between the ROS1- positive and negative groups. The in vitro studies showed evidence of sensitivity to crizotinib. Finally, the authors reported the clinical response of one patient in their study with a ROS1 rearrangement. The patient was enrolled as part of an expanded phase 1 cohort, in an open-label, multicenter trial of crizotinib. The patient had no EGFR mutation or ALK rearrangement. After treatment failure with erlotinib, the patient was treated with crizotinib and had near complete resolution of tumor without evidence of recurrence at 6 months.
Kim and colleagues reported clinical outcomes in 208 never-smokers with NSCLC adenocarcinoma, according to ROS1-rearrangement status (Kim, 2013). ALK rearrangements and EGFR mutations were concurrently analyzed. The patients had clinical stages ranging from I-IV, but the majority were stage IV (41.3%). Of the 208 tumors, 3.4% (n=7) were ROS1 rearranged. ROS1 rearrangement was mutually exclusive from ALK rearrangement, but 1 of 7 ROS1-positive patients had a concurrent EGFR mutation.
Patients with ROS1 rearrangement had a higher objective response rate and longer median PFS on pemetrexed than those without a rearrangement. In patients with ROS1 rearrangement, PFS with EGFR-tyrosine kinase inhibitors was shorter than those patients without the rearrangement. None of the ROS1 positive patients received ALK inhibitors (eg, crizotinib), which is the proposed targeted therapy for patients with NSCLC and this genetic alteration.
RET
In a phase 2 prospective trial for patients with RET fusion-positive tumors, preliminary data on 3 patients treated with cabozantinib showed a partial response in 2 patients, and 1 with stable disease approaching
8 months (Drilon, 2013).
MET
A phase 2 trial of MET-positive NSCLC, in which patients were treated with an anti-MET antibody plus erlotinib, showed improved progression-free survival and overall survival (Sadiq, 2013).
BRAF
Rare case reports have documented a response to vemurafenib in patients with NSCLC and a BRAF mutation (Gautschi, 2012; Peters, 2013; Robinson, 2014).
HER2
Mazières and colleagues reported on a retrospective review of a consecutive series of patients with
NSCLC who were tested for a HER2 mutation, and the authors assessed clinicopathologic characteristics and patient outcomes according to mutation status (Mazieres, 2013). A HER2 mutation was identified in 65 of 3,800 (1.7%) patients, and was mutually exclusive of other driver mutations (EGFR, ALK and BRAF), with the exception of one case in which both a HER2 and KRAS mutation were identified. The patient population in which a HER2 mutation was found had a median age of 60 years (range 31 to 86), 69% were women, and 52% were never smokers. All of the tumors were adenocarcinomas, and 50% were stage IV (n=33). The patients with stage IV disease received conventional chemotherapy, and of these, 16 patients also received HER2-targeted therapy as additional lines of therapy (for a total of 22 individual anti-HER2 treatments that were evaluable). Four patients had progressive disease, 7 had disease stabilization, and 11 with partial response. PFS for patients with HER2 therapies was 5.1 months.
Summary
Over half of patients with non-small cell lung cancer (NSCLC) present with advanced and therefore incurable disease, and treatment in this setting has generally been with platinum-based chemotherapy.
More recently, 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.
In NSCLC, the first successful example of targeted therapy involved mutations in the epidermal growth factor receptor (EGFR) gene, in which lung tumors harboring specific activating mutations in the EGFR kinase domain showed a high sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Phase 3 studies comparing EGFR-TKIs to chemotherapy in patients with EGFR-mutated NSCLC have shown that TKIs are superior to chemotherapy in terms of tumor response rate and progression free survival, with a reduction in toxicity and improvement in quality of life.
Currently, routine testing of NSCLC for EGFR mutations is recommended in patients with non-squamous
NSCLC, since TKIs are recommended if the tumor has an EGFR mutation.
Therefore, EGFR mutational analysis may be considered medically necessary to predict treatment response to erlotinib or afatinib in patients with advanced NSCLC; however, EGFR mutational analysis is investigational in patients with NSCLC of squamous cell type.
KRAS mutations may be prognostic in NSCLC and may predict a lack of response to TKIs, but the impact of testing for these mutations on clinical management is unknown. Studies have not shown that KRAS mutations identify a population that may benefit from the use of anti-EGFR monoclonal antibodies. Therefore, 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 inhibitors erlotinib and the anti-EGFR monoclonal antibody cetuximab in non-small-cell lung carcinoma.
Other, potentially targetable oncogenic mutations have been characterized in lung adenocarcinomas, including in the genes ROS, RET, MET, BRAF and HER2. The data on the use of targeted therapies in NSCLC with a mutation in one of these genes is preliminary, in that much of the demonstrated sensitivity of tumor to the various drugs has been in vitro or in animal studies, and published data on patient tumor response and survival outcomes are extremely limited, consisting of case reports and small case series. Therefore, testing for genetic alterations in the genes ROS, RET, MET, BRAF and HER2, for targeted therapy in patients with NSCLC, is considered investigational.
National Comprehensive Cancer Network (NCCN) Guidelines
NCCN guidelines for the treatment of NSCLC (version 4.2014) recommend the following:
EGFR mutation testing is recommended (category 1) in patients with non-squamous 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 mutations.
Erlotinib is recommended as first-line therapy in patients with sensitizing EGFR mutations and should not be given as first-line therapy to patients negative for these EGFR mutations or with unknown EGFR status. Afatinib is recommended as first- or second-line therapy “for select patients with sensitizing EGFR mutations.” In patients with squamous cell carcinoma, EGFR mutation testing should be considered “especially in” never smokers; when histology is assessed using small biopsy specimens (rather than surgically resected samples); or when histology is mixed adenosquamous.
NCCN states 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”.
NCCN does not give specific recommendations for testing for genetic alterations in the genes ROS, RET,
MET, BRAF or HER2 in NSCLC, however, they state that the following targeted agents are now recommended for patients with specific genetic alterations: afatinib, cabozantinib, crizotinib, dabrafenib, erlotinib, gefitinib, trastuzumab and vemurafenib (category 2A).
American Society of Clinical Oncology Provisional Clinical Opinion
In 2011, the American Society of Clinical Oncology issued a provisional clinical opinion on EGFR mutation testing for patients with advanced NSCLC who are considering first-line EGFR tyrosine kinase inhibitor therapy (Keedy, 2011). The authors concluded that such patients who have not previously received chemotherapy or an EGFR tyrosine kinase inhibitor (TKI) should undergo EGFR mutation testing to determine whether chemotherapy or an EGFR TKI is appropriate first-line treatment.
College of American Pathologists Joint Guideline
In 2013, the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology published evidence-based guidelines for molecular testing to select patients with lung cancer for treatment with EGFR TKI therapy (Lindeman, 2013). Based on excellent quality evidence (category A), the guidelines recommend EGFR mutation testing in patients with lung adenocarcinoma regardless of clinical characteristics, such as smoking history. Guidelines for EGFR mutation testing in patients with SCC are reviewed in the Rationale section of the policy (see EGFR Mutation Frequency).
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 (Socinski, 2013). Based on their review of the literature, guideline authors reported improved response rates, PFS, and toxicity profiles with first-line erlotinib or gefitinib compared with firstline platinum-based therapy in patients with EGFR mutations, especially exon 19 deletion and L858R. ACCP recommends “testing patients with NSCLC for EGFR mutations at the time of diagnosis whenever feasible, and treating with first-line EGFR TKIs if mutation-positive.”
2015 Update
This policy is being updated with a literature search using the MEDLINE database through April 2015. This update focuses on analysis of somatic rearrangement mutation of the ALK gene.
The accelerated approval of crizotinib by the FDA was based on phase 1 and 2 trials in which crizotinib showed marked antitumor activity in patients with ALK-positive advanced NSCLC, with objective response rates of 60% and PFS of 7 to 10 months (Camidge, 2012; Kwak, 2010). These results were confirmed in 2 subsequent phase 3 trials.
A phase 3, open-label trial randomized 347 patients with previously treated, locally advanced or metastatic ALK-positive lung cancer to oral crizotinib twice daily (n=173) or chemotherapy (n=174) every 3 weeks (Shaw, 2013). All patients had received one platinum-based chemotherapy regimen prior to the trial. The extent of disease was metastatic in 95% and 91% of patients in the crizotinib and chemotherapy groups, respectively, and tumor histology was adenocarcinoma in 95% and 94%, respectively. The primary endpoint was PFS. Patients in the chemotherapy group who experienced progressive disease were allowed to cross over to receive crizotinib as part of a separate study. Median PFS was 7.7 months in the crizotinib group versus 3.0 months in the chemotherapy group (HR for progression or death with crizotinib, 0.49; 95% CI 0.37 to 0.64; p<0.001). Partial response rates with crizotinib were 65% (95% CI, 58 to 72), versus 20% (95% CI, 14 to 26) with chemotherapy (p<0.001). Interim analysis of OS showed no significant improvement with crizotinib compared with chemotherapy (HR for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; p=0.54). Median follow-up for OS was 12.2 months and 12.1 months in the crizotinib and chemotherapy groups, respectively. Patients reported greater reductions in lung cancer symptoms and greater improvement in global quality of life with crizotinib compared with chemotherapy.
A phase 3, open-label trial compared crizotinib and chemotherapy in 343 previously untreated patients with ALK-positive advanced non-squamous NSCLC (Solomon, 2014). Patients were randomized to oral crizotinib twice daily or pemetrexed with either cisplatin or carboplatin every three weeks for up to 6 cycles. If there was disease progression for patients receiving chemotherapy, crossover to crizotinib was allowed. PFS was the primary end point. PFS was 10.9 months compared to 7.0 months for the group that received crizotinib versus chemotherapy, respectively (HR for progression or death with crizotinib, 0.45; 95% CI 0.35 to 0.60; p<0.001); objective response rates (complete and partial responses) were 74% and 45%, respectively (p<0.001). Median OS was not reached in either group; the probability of 1-year survival with crizotinib was 84% and with chemotherapy 79%. Crizotinib was associated with patient reported greater reduction in lung cancer symptoms and greater improvements in quality of life.
Crizotinib was granted accelerated approval by FDA in August 2011, for patients with locally advanced or metastatic NSCLC, based on objective response rates observed in 2, single-arm trials. Two subsequent phase 3 trials showed superior PFS and tumor response rates and improved quality of life in patients with crizotinib versus chemotherapy, in both previously untreated, ALK-positive advanced NSCLC and in patients who had received previous chemotherapy.
NCCN Guidelines
NCCN (v.4.2015) states that ALK rearrangement testing is recommended (category 1) in patients with non-squamous NSCLC (ie, adenocarcinoma, large cell carcinoma) or in NSCLC not otherwise specified, because crizotinib (category 1) is recommended for patients who are positive for ALK rearrangements. If ALK-positive status is discovered prior to first-line chemotherapy, give crizotinib (category 1), or if ALK rearrangement is discovered during first-line chemotherapy, interrupt or complete planned chemotherapy and start crizotinib. If there is progression on crizotinib, NCCN guidelines recommend multiple options (category 2A) including continuing crizotinib, switching to ceritinib, and considering local therapies depending upon symptoms.
2017 Update
A literature search conducted through September 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Clinical Validity
EGFR-sensitizing and resistance variants can be detected by direct sequencing, or polymerase chain reaction (PCR) technologies, or next generation sequencing (NGS). Gene sequencing is considered an analytic criterion standard. In 2010, the Canadian Agency for Drugs and Technologies in Health published a rapid response report on EGFR mutation variant analysis (Mojoomdar, 2010). Based on 11 observational studies, the report authors concluded that PCR-based approaches identify EGFR mutations variants with a sensitivity equivalent to that of direct sequencing
Four tests have been approved as companion diagnostics to detect EGFR-resistance variants (exon 19 deletions or exon 21 L858R substitutions) for at least one of the EGFR TKIs (afatinib, erlotinib, or gefitinib): the therascreen EGFR Rotor-Gene Q polymerase chain reaction (RGQ PCR) kit, cobas EGFR Mutation Test v1 and v2, Oncomine Dx Target Test. The cobas v2 test also is approved as a companion diagnostic to detect the T790M resistance variant to select patients for treatment with osimertinib.
The clinical validity of the therascreen RGQ PCR kit was demonstrated in a retrospective analysis of patients screened for a phase 3, open-label randomized controlled trial (RCT) comparing afatinib with chemotherapy in treatment-naive patients with stage IIIB or IV NSCLC, in which the EGFR variants for enrollment were determined using a Clinical Trial Assay (CTA) conducted at central laboratories (FDA, 2013/P120022b). The positive percent agreement (PPA) of therascreen vs CTA for detection of EGFR-sensitizing variants was 98% (95% confidence interval [CI], 95% to 99%) and negative percent agreement (NPA) was 97% (95%
CI, 94% to 99%). Overall, a statistically significant efficacy benefit for afatinib vs chemotherapy was
The clinical validity of the cobas EGFR Mutation Test v1 was demonstrated in a retrospective analysis of patients screened for a phase 3, open-label RCT comparing erlotinib with chemotherapy in treatment-naïve patients with advanced NSCLC. In this RCT, the EGFR variants for enrollment were determined with a CTA at a central laboratory using Sanger sequencing first for determination of EGFR variants status, followed by confirmatory testing for exon 19 deletions and exon 21 L858R variants (FDA, 2013/P120019b). The PPA of cobas vs CTA for detection of EGFR-sensitizing variants was 94% (95% CI, 89% to 97%) and NPA was -98% (95% CI, 95% to 99%). Overall, a statistically significant efficacy benefit for erlotinib vs chemotherapy was reported in the EGFR-positive patients as measured by the cobas EGFR Mutation Test v1 (HR=0.34; 95% CI, 0.21 to 0.54) that was similar to the efficacy in the overall population, which was EGFR-positive by the CTA (HR=0.34; 95% CI, 0.23 to 0.49). The cobas EGFR Mutation Test v2 expanded the indication for the use of the cobas EGFR Mutation Test to add the detection of the exon 20 (T790M) substitution variant in NSCLC patients for whom Tagrisso (osimertinib) treatment is indicated (FDA, v2 2015/P120019S007b). The clinical validity of the cobas EGFR Mutation Test v2 was demonstrated in retrospective analyses of patients enrolled in a phase 2, single-arm study of osimertinib for EGFR-sensitizing variant-positive metastatic NSCLC who had progressed following prior therapy with an approved EGFR TKI The osimertinib response rate in the patients identified as EGFR T790M+ by the cobas v2 test was 62% (95 % CI, 55% to 69%).
Similar results were reported in another phase 3 trial conducted in 364 Asian patients (Lux-Lung 6) comparing afatinib with gemcitabine plus cisplatin (Wu, 2014). PFS was 11.0 in the afatinib group and 5.6 months in the chemotherapy group (HR=0.28; 95% CI, 0.20 to 0.39) and the response rate was 67% and 23%.
Comparative Effectiveness of EGFR TKIs
As the previous sections have shown, erlotinib, gefitinib, and afatinib all have improved efficacy compared with chemotherapy in patients who have NSCLC and EGFR-sensitizing variants and are well tolerated. RCTs directly comparing the EGFR TKIs have been conducted.
Yang and colleagues published a systematic review and meta-analysis of studies comparing erlotinib, gefitinib, and afatinib (Yang, 2017). Eight randomized trials (N=2225 patients) and 82 cohort studies (N=15,396 patients) were included. However, results were not presented for trials vs cohort studies separately. Of the 8 RCTs identified, three were published in journals not available through PubMed, one was available as an abstract only, one was conducted in squamous cell NSCLC, and one did not require testing to confirm EGFR variant status for enrollment; these RCTs will not be discussed further (Park, 2016; Urata, 2016).
Two RCTs have compared gefitinib and erlotinib in patients with EGFR-sensitizing variants. Urata et al (2016) reported on a phase 3 RCT of 401 patients with EGFR variants randomized to gefitinib or erlotinib (Urata, 2016). The median PFS was 8.3 months (95% CI, 7.2 to 9.7 months) for patients receiving gefitinib and 10.0 months for those receiving erlotinib (95% CI, 8.5 to 11.2 months). Rash was more common with erlotinib (18.1% vs 2.2%) while both alanine aminotransferase elevation and aspartate aminotransferase elevation were more common with gefitinib (6.1% vs 2.2% and 13.0% vs 3.3%, respectively). Similarly, Yang and colleagues reported a median PFS of 13.0 for erlotinib and 10.4 months for gefitinib (HR=0.81; 95% CI, 0.62 to 1.05) in 256 patients with no differences in rates of grade 3 of 4 adverse events (Yang, 2017).
ALK GENE REARRANGEMENTS
Clinical Validity
Several methods are available to detect ALK gene rearrangements or the resulting fusion proteins in tumor specimens including fluorescence in situ hybridization (FISH), immunohistochemistry, reverse transcription polymerase chain reaction of cDNA (RT-PCR) and NGS. Two tests have been approved by the FDA as companion diagnostics to detect ALK rearrangements for treatment with crizotinib: the Vysis ALK Break Apart FISH Probe Kit and Ventana ALK (D5F3) CDx Assay.
The Vysis kit is a FISH-based assay. The clinical validity of the Vysis ALK Break Apart FISH Probe Kit was demonstrated in a retrospective analysis of patients screened for a phase 2, open-label single-arm study of crizotinib in patients with stage IIIB or IV NSCLC (FDA, 2011/p110012B). The response rate for crizotinib in 136 ALK-positive patients was 50% (95% CI, 42% to 59%) with a median duration of response of 42 weeks (range, 6-42). The response rate for 19 ALK-negative patients was 26% (95% CI, 9% to 51%).
The Ventana assay is an ICH-based assay. The clinical validity of the Ventana ALK (D5F3) CDx Assay was demonstrated in a retrospective analysis of patients screened for an open-label RCT of crizotinib vs platinum-doublet chemotherapy in patients with stage IIIB/IV NSCLC (FDA, 2015/PP140025B). The concordance between the Ventana and Vysis tests were calculated using patient samples analyzed at an independent, central laboratory. The PPA was 86.0% (95% CI, 80.2% to 90.4%) and the NPA was 96.3% (94.7% to 97.4%). Overall, in 343 patients who were ALK-positive by the Vysis assay, crizotinib was associated with longer PFS compared with chemotherapy (HR=0.45; 95% CI, 0.36 to 0.60). In the subset of 141 patients who were also ALK-positive by the Ventana assay, the results were similar (HR=0.40; 95% CI, 0.25 to 0.64). In the 25 patients that were ALK-positive by the Vysis assay and ALK-negative by the Ventana assay, the relative effect of crizotinib was not clear (HR=1.71; 95% CI, 0.43 to 6.79).
Other ALK Inhibitors
Three other ALK TKIs are FDA-approved but without separate companion diagnostics. Ceritinib has demonstrated superior efficacy concerning PFS when compared with chemotherapy in both the first-line and second-line (following crizotinib) settings in the ASCEND-4 and ASCEND-5 RCTs (Shaw, 2017; Soria, 2017). Alectinib was associated with response rates of approximately 50% in patients who had progressed on crizotinib in 2 phase 2 studies (Ou, 2016; Shaw, 2016). Alectinib has also shown superior efficacy and lower toxicity when compared with crizotinib in the first-line setting in the ALEX and J-ALEX phase 3 RCTs (Hida, 2017; Peters, 2017). Brigatinib has shown promise in early phase 1 and phase 2 studies with PFS of almost 13 months in patients with crizotinib-refractory disease (Gettinger, 2016; Kim, 2017).
ROS GENE REARRANGEMENTS
Clinical Validity
Several methods are available to detect ROS1 translocations including FISH, immunohistochemistry, and quantitative real-time reverse transcription-PCR (qRT-PCR) and some NGS panels. FISH is considered the standard method. The Oncomine Dx Target Test was FDA-approved in 2017 as a companion diagnostic to detect fusions in ROS1 to aid in selecting NSCLC patients for treatment with Xalkori (crizotinib). The Oncomine test is an NGS oncology panel that detects, among other variants, fusions in ROS1 from RNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples (FDA, 2017/P160045b). The clinical validity of the detection of ROS1 rearrangements by the test was evaluated by retrospective analysis of FFPE NSCLC specimens obtained from patients enrolled in a ROS1 cohort from an ongoing single-arm, phase 1 safety, study of crizotinib in patients with advanced cancer. The ROS1 fusion status was determined by a validated FISH comparator test for the study. Concordances between the Oncomine Dx Target Test and the FISH test as well as clinical outcomes were reported in the Summary of Safety and Effectiveness Data. A total of 157 specimens were included. The PPA for Oncomine vs FISH was 80% (95% CI, 59 to 93) and NPA was 100% (95% CI, 97 to 100). For all ROS1-positive patients, as originally detected for enrollment into the ROS1 cohort, the response rate was 72% (95% CI, 58% to 84%). For ROS1-positive patients as detected by Oncomine, the response rate was 83% (95% CI, 36% to 99.6%).
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