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| Genetic Test: Melanoma and Glioma, Testing to Predict Response to Targeted Therapy | |
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| Description: |
Multiple biomarkers are being evaluated to select treatment with an FDA-approved targeted treatments for patients with unresectable, recurrent, relapsed, refractory, advanced or metastatic cancer. These include tissue-based testing as well as circulating tumor DNA (known as liquid biopsy).
Gene Variants Found in DNA for Targeted Therapy
ALK Gene
ALK is a tyrosine kinase (TK) that, in NSCLC, is aberrantly activated because of a chromosomal rearrangement that leads to a fusion gene and expression of a protein with constitutive TK 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. The most common variant locus is found in codon 600 of exon 15 (V600E) of the BRAF gene, causing constitutive hyperactivation, proliferation, differentiation, survival, and oncogenic transformation (Wang, 2022). BRAF variants occur in approximately 1% of breast cancer cases (Albanell, 2016).,Variants in the b-raf proto-oncogene, serine/threonine kinase (BRAF) kinase gene are common in tumors of patients with advanced melanoma and result in constitutive activation of a key signaling pathway (rapidly accelerated fibrosarcoma [RAF]-MEK-extracellular signal-regulated kinase [ERK] pathway) that is associated with oncogenic proliferation. In general, 50% to 70% of melanoma tumors harbor a BRAF variant; of these, 80% are positive for the BRAF V600E variant, and 16% are positive for BRAF V600K (Vultur, 2011). Thus, 45% to 60% of advanced melanoma patients may respond to a BRAF inhibitor targeted to this mutated kinase. There is considerable interest in targeted therapies that inhibit the RAF-MEK-ERK pathway, particularly in patients with high-grade and low-grade gliomas whose tumors are in locations that prevent full resection. Evidence from early-phase trials in patients with BRAF variant-positive melanoma with brain metastases have suggested some efficacy for brain tumor response with vemurafenib and dabrafenib indicating that these agents might be potential therapies for primary brain tumors (Dummer, 2014; Long, 2012). 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.
BRCA Variant Testing
The prevalence of BRCA variants is approximately 0.2% to 0.3% in the general population (Nelson, 2019). The prevalence may be much higher for particular ethnic groups with characterized founder variants (e.g., 2.5% [1/40] in the Ashkenazi Jewish population). Family history of breast and ovarian cancer is an important risk factor for the BRCA variant; additionally, age and ethnicity could be independent risk factors.
Several genetic syndromes with an autosomal dominant pattern of inheritance that features breast cancer have been identified (Hemel, 2010). Of these, hereditary breast and ovarian cancer (HBOC) and some cases of hereditary site-specific breast cancer have in common causative variants in BRCA (breast cancer susceptibility) genes. Families suspected of having HBOC syndrome are characterized by an increased susceptibility to breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian cancer at any age, as well as cancer of the fallopian tube and primary peritoneal cancer. Other cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer, occur more frequently in HBOC families. Hereditary site-specific breast cancer families are characterized by early-onset breast cancer with or without male cases, but without ovarian cancer. For this evidence review, BCBSA refers collectively to both as hereditary breast and/or ovarian cancer.
Germline variants in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in most HBOC families, especially if ovarian cancer or male breast cancer are features (Yoshida, 2021). However, in site-specific cancer, BRCA variants are responsible only for a proportion of affected families. BRCA gene variants are inherited in an autosomal dominant fashion through maternal or paternal lineage. It is possible to test for abnormalities in BRCA1 and BRCA2 genes to identify the specific variant in cancer cases and to identify family members at increased cancer risk. Family members without existing cancer who are found to have BRCA variants can consider preventive interventions for reducing risk and mortality.
Young age of onset of breast cancer, even in the absence of family history, is a risk factor for BRCA1 variants. Winchester estimated that hereditary breast cancers account for 36% to 85% of patients diagnosed before age 30 (Winchester, 1996). In several studies, BRCA variants were independently predicted by early age at onset, being present in 6% to 10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (age range, 35-50 years) (Winchester, 1996; Frank, 2002; Langston, 1996; Malone, 1998). In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 variants is in the 40s (Ford, 1998). In the Ashkenazi Jewish population, Frank et al reported that 13% of 248 cases with no known family history and diagnosed before 50 years of age had BRCA variants (Frank, 2002). In a similar study by Gershoni-Baruch et al, 31% of Ashkenazi Jewish women, unselected for family history, diagnosed with breast cancer at younger than 42 years of age had BRCA variants (Gershoni, 2000). Other studies have indicated that early age of breast cancer diagnosis is a significant predictor of BRCA variants in the absence of family history in this population (Warner, 1999; Hartge, 1999; Hodgson, 1999).
In patients with “triple-negative” breast cancer (i.e., negative for expression of estrogen, progesterone, and overexpression of human epidermal growth factor receptor 2 [HER2] receptors), there is an increased prevalence of BRCA variants. Pathophysiologic research has suggested that the physiologic pathway for the development of triple-negative breast cancer is similar to that for BRCA-associated breast cancer (de Ruijter, 2011). Young et al studied 54 women with high-grade, triple-negative breast cancer with no family history of breast or ovarian cancer, representing a group that previously was not recommended for BRCA testing (Young, 2009). Six BRCA variants (5 BRCA1, 1 BRCA2) were found, for a variant rate of 11%. Finally, Gonzalez-Angulo et al in a study of 77 patients with triple-negative breast cancer, reported that 15 patients (19.5%) had BRCA variants (12 in BRCA1, 3 in BRCA2) (Gonzalez-Angulo, 2011).
CLDN18
Claudin-18 (CLDN18) is a transmembrane protein that forms tight junctions between epithelial cells and regulate the flow and movement of ions across epithelial cells. Overexpression of this protein is implicated in the development of various primary malignant tumors, such as gastric cancer/gastroesophageal junction (GC/GEJ) cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer, and non-small-cell lung cancer (Cao, 2022; Huang, 2025). More specifically, CLDN18.2 is an isoform that is exclusively expressed in the tight junctions of gastric mucosal cells and participates in the proliferation, differentiation and migration of tumor cells. Studies have reported that CLDN18.2 is expressed in approximately 70% of gastric cancers and up to 60% of pancreatic adenocarcinomas (Tojiari, 2024).
EGFR
EGFR, a receptor tyrosine kinase (TK), is frequently overexpressed and activated in NSCLC. Drugs that inhibit EGFR signaling either prevent ligand binding to the extracellular domain (monoclonal antibodies) or inhibit intracellular TK activity (small-molecule tyrosine kinase inhibitors [TKIs]). These targeted therapies dampen signal transduction through pathways downstream to the EGFR, such as the RAS/RAF/MAPK cascade. RAS proteins are G proteins that cycle between active and inactive forms in response to stimulation from cell surface receptors, such as EGFR, acting as binary switches between cell surface EGFR and downstream signaling pathways. These pathways are important in cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.
Somatic variants 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) are the most commonly found EGFR variants associated with sensitivity to EGFR 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 exon 20.
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).
ESR1
Variants in estrogen receptor 1 (ESR1), which occur in approximately 10-20% of patients with metastatic estrogen receptor-positive breast cancer, confer resistance to endocrine therapy via constitutive activation of estrogen receptor-mediated growth activity (Toy, 2013; Jeselsohn, 2014).
EZH2
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltrasnferase responsible for generating epigenetic markers that regulate gene function with the most common being trimethylation of Lys-27 in histone 3 (H3K27me3) (Duan, 2020). EZH2 is overexpressed in numerous tumor types including melanoma, ovarian, breast, endometrial, bladder, renal cell, lung, and liver cancer, and is associated with aggressive disease, leading to its classification as an oncogene. It is commonly overexpressed or harbors gain-of-function mutations that enhance the catalytic activity within 25 percent of follicular lymphomas (Romero, 2024).
FGFR2 and FGFR3
The fibroblast growth factor receptor (FGFR) family is an integral signaling pathway for cellular activities, including proliferation, tissue repair, regeneration, chemotaxis, angiogenesis, differentiation, and survival (Seraji, 2025). Thus, dysregulation of this pathway with alterations of these genes has been implicated in numerous cancers, including uroepithelial carcinoma (32–14.8%), colorectal carcinoma (31%), breast carcinoma (12.6–18%), gastric carcinoma (16.8–25.6%), endometrial carcinoma (13%), squamous lung carcinoma (6.8–13%), esophageal carcinoma (12.7%), ovarian carcinoma (9%), and lung adenocarcinoma (1.3%). Most of these abnormalities were gene amplifications (53.7–66%), followed by mutations (26–38.8%), and rearrangements/fusions (5.6–8%). The frequencies of aberration for FGFR2 and FGFR3 were 14.2–19% and 17.7–26%, respectively (Zhang, 2024; Du, 2023).
FLT3 (ITD/TDK)
Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 25% to 30% of acute myeloid leukemia (AML) cases and results in more severe outcomes, including higher relapse rates and reduced overall survival, after standard of care treatment (Fedorov, 2023; Rataj, 2025; Tamburini, 2023). Variants in FLT3 were found in 30% of newly diagnosed AML patients, with FLT3-ITD variants occurring with a frequency of 24% and variants within the activation loop (FLT3-TKD mutations) occurring at a frequency of 7%.
FOLR1
Folate receptor alpha, encoded by the FOLR1 gene, is an attractive target for cancer therapeutics due to its high expression in several cancer types including lung, breast, and epithelial ovarian cancer (EOC) with overexpression in approximately 80% of EOCs (Mai, 2023).
Homologous Recombination Deficiency and Homologous Recombination Repair
DNA damage happens daily, and most are repaired to allow normal cell functioning. Double strand breaks (DSB) in the DNA are particularly damaging. Repair of DSB utilizes the homologous recombination repair (HRR) pathway. Many types of cancer, however, are unable to repair DNA damage. This leads to the accumulation of genetic errors, such as loss of DNA, rearrangements in the DNA, and loss of entire genes. The consequence of these errors is genomic instability. The loss of the HRR and associated genomic instability is called homologous recombination deficiency (HRD). HRD is associated with several types of cancer including ovarian cancer (NCI, 2026: Mateo, 2017). HRD is associated with several types of cancer including prostate cancer, where estimates as high as 30% of metastatic castrate-resistant prostate cancer (mCRPC) tumors have genetic changes that result in the loss of DNA repair capacity (Mateo, 2017). Specific to prostate cancer, the National Comprehensive Cancer Network (NCCN) prostate cancer guideline gives examples of HRR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) (NCCN, 2026). Poly adenosine diphosphate-ribose polymerase (PARP) inhibitors are used to target tumor cells with alterations in the HRR genes BRCA1 and BRCA2.
In ovarian cancer targeted therapies, HRD-positive status is generally defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. Myriad MyChoice is an FDA-approved companion diagnostic for the assessment of tumor genomic instability score (GIS) and the detection and classification of variants in the BRCA1 and BRCA2 genes, for the selection of patients who are eligible for targeted treatment. A patient’s Myriad HRD status is determined by detecting single nucleotide variants (SNVs), variants in homopolymer stretches, insertions and deletions (indels), and large rearrangements (LRs) in the BRCA1 and BRCA2 genes, and determining a genomic instability score (GIS) using DNA obtained from ovarian tumor tissue. A positive Myriad HRD Status result is due to either the presence of a pathogenic variant in BRCA1 and/or BRCA2 and/or a GIS above a defined threshold (Myriad Genetics, 2024). Approximately 41% to 50% of epithelial ovarian cancers are estimated to exhibit HRD. Germline alterations in BRCA1 and BRCA2 genes have been identified in up to 17% of individuals diagnosed with epithelial ovarian cancer, and somatic mutations are found in an additional 7% (Tew, 2022).
Human Epidermal Growth Factor Receptor 2 Amplification/Overexpression
Human epidermal growth factor receptor 2 (HER2) is a member of the HER (EGFR) family of tyrosine kinase receptors and has no specific ligand. When activated, it forms dimers with other EGFR family members. Amplification of HER2 is detected in approximately 4% of patients with CRC, with higher prevalence in RAS/BRAF-wild type tumors (5% to 14%) (Singh, 2024). In addition to its role as a predictive marker for HER2-targeted therapy, HER2 amplification/overexpression is being investigated as a predictor of resistance to EGFR-targeting monoclonal antibodies.
Human Leukocyte Antigen
The human leukocyte antigen (HLA) is a complex system of genes in humans that encode cell-surface proteins responsible for the regulation of the immune system. HLA molecular pathways present tumor antigens to T-cells to facilitate the recognition of tumor cells by the immune system. HLA genes are highly polymorphic allowing them to fine-tune the immune response through multiple unique combinations. HLA variants are crucial for targeted therapy as these drugs are engineered to bind to specific HLA constructs to evoke an immune response against tumor cells (Wang, 2020).
IDH1 and IDH2
Mutations in isocitrate dehydrogenase-1 (IDH1) or -2 (IDH2) genes lead to aberrant accumulated production of D-2-hydroxyglutarate, disrupting gene expression and cellular differentiation. WHO grade 2 and 3 astrocytomas and oligodendrogliomas are defined by IDH mutations, distinguishing lower-grade gliomas from glioblastomas. IDH1 and IDH2 mutations are generally associated with a more favorable prognosis, and have been important biomarkers for stratification in clinical trials. IDH mutations are detected in over 50% of gliomas in patients aged 55 or older (NCCN, 2026).
KIT
KIT, also known as c-KIT, is a tyrosine kinase expressed on the surface of cells and plays a significant role in cell survival, proliferation, and differentiation via signaling pathways. For instance, KIT signaling is required for melanocyte survival, and is involved in hematopoiesis and gametogenesis. Gain-of-function variants within this gene are highly associated with cancer as it is implicated in numerous signaling pathways, such as RAS-MAPK and PI-3K.KIT variants are present in 85% to 95% of gastrointestinal stromal tumors (GIST) and systemic mastocytosis cancers (Heinrich, 2003).
KMT2A
Lysine methyltransferase 2A (KMT2A), located at chromosome 11q23, encodes a histone H3 lysine 4 methyltransferase that functions as an epigenetic regulator of hematopoietic stem cell self-renewal through control of HOX-A and MEIS1 transcription. Chromosomal rearrangements at the KMT2A locus generate in-frame fusion proteins joining the N-terminus of KMT2A to one of more than 90 documented partner genes (most commonly MLLT3, MLLT10, AFDN, ELL, and MLLT1) that drive aberrant upregulation of HOX-A and MEIS1 to arrest myeloid differentiation. KMT2A rearrangements (KMT2A-r) are identified in approximately 5% to 10% of de novo adult acute myeloid leukemia (AML) and at substantially higher frequencies in pediatric AML, reaching 50% to 60% in infants under 2 years of age (Testa, 2026).
MET
MET alteration is one of the critical events for acquired resistance in EGFR-mutated adenocarcinomas refractory to EGFR TKIs (Thunnissen, 2014).
Mismatch Repair Deficiency/Microsatellite Instability
Mismatch repair deficiency (dMMR) and high levels of microsatellite instability (MSI-H) describe cells that have alterations in certain genes involved in correcting errors made when DNA is replicated. dMMR tumors are characterized by a high tumor mutational load and potential responsiveness to anti-programmed cell death ligand-1 (PD-L1)-immunotherapy. Mismatch repair (MMR) deficiency is most common in colorectal cancer, other types of gastrointestinal cancer, and endometrial cancer, but it may also be found in other cancers including breast cancer.
Testing for dMMR and MSI is used to identify individuals most likely to respond to anti-PD-L1 therapy. Either MMR testing or MSI testing can be used to screen for MMR functional defects. MMR testing is performed using IHC for 4 MMR proteins (MLH1, MSH2, PMS2, and MSH6). Microsatellite instability testing is generally performed using polymerase chain reaction (PCR) for 5 biomarkers (MLH1, MSH2, MSH6, PMS1 and PMS2). High MSI is defined as 2 or more of the 5 biomarkers showing instability or more than 30% of the tested biomarkers showing instability depending on what panel is used (Bonneville, 2020).
Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion Testing
The presence of NTRK gene fusion can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry (TRK Fusion Cancer, 2025). Next-generation sequencing provides the most comprehensive view of a large number of genes and may identify NTRK gene fusions as well as other actionable alterations, with minimal tissue needed. The fluorescence in situ hybridization using break-apart probes can detect gene rearrangements in DNA that may generate a fusion transcript. The immunohistochemistry techniques have generally been used in the research setting. Reverse transcription-polymerase chain reaction is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners.
PIK3CA Testing
Alterations in the protein coding gene PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) occur in approximately 40% of patients with hormone receptor (HR)-positive, HER2-negative breast cancer. (Karakas, 2006).
Platelet-Derived Growth Factor Receptor Alpha and Beta
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors and are members of the platelet-derived growth factor (PDGF) family. PDGF subunits alpha and beta play important roles in regulating cell proliferation, cellular differentiation, cell growth and development with alterations in these genes being heavily implicated in oncogenesis. PDGFRA variants occur in approximately 10–15% of GISTs, however, PDGFRB rearrangements are rare with approximately 2% of myeloproliferative neoplasms containing these fusions (Sun, 2022; Ondrejka, 2014).
Programmed Cell Death Ligand Protein-1
Programmed cell death ligand-1 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.
FDA-approved PD-L1 immune checkpoint inhibitors include atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.
RAS (KRAS and NRAS)
Cetuximab (Erbitux; ImClone Systems) and panitumumab (Vectibix; Amgen) are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing intrinsic ligand binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization. The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. The RAS proteins are G proteins that cycle between active (RAS guanosine triphosphate) and inactive (RAS guanosine diphosphate) forms in response to stimulation from a cell surface receptor, such as EGFR, and they act as a binary switch between the cell surface EGFR and downstream signaling pathways. The KRAS gene can harbor oncogenic variants that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. Approximately 40% of colorectal cancers (CRCs) have KRAS variants in codons 12 and 13 in exon 2. Another proto-oncogene that acts downstream from KRAS-NRAS harbors oncogenic variants in codons 12, 13, or 61 that result in constitutive activation of the EGFR-mediated pathway. These variants are less common compared with KRAS, detected in 2% to 7% of CRC specimens. It is unclear whether NRAS variants predict poor response due to anti-EGFR monoclonal antibody therapy or are prognostic of poor CRC outcomes in general.
The KRAS gene (which encodes RAS proteins) can harbor oncogenic variants that result in a constitutively activated protein, independent of signaling from the EGFR, possibly rendering a tumor resistant to therapies that target the EGFR. Variants in the KRAS gene, mainly codons 12 and 13, have been reported in 20% to 30% of NSCLC, and occur most often in adenocarcinomas in heavy smokers. KRAS variants can be detected by direct sequencing, polymerase chain reaction technologies, or next-generation sequencing. EGFR, ALK, ROS1, and KRAS driver mutations are considered to be mutually exclusive.
A large body of literature has shown that metastatic CRC tumors with a variant in exon 2 (codon 12 or 13) of the KRAS gene do not respond to cetuximab or panitumumab therapy. More recent evidence has shown that variants in KRAS outside exon 2 (i.e., in exons 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) and variants in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) also predict a lack of response to these monoclonal antibodies. Variant testing of these exons outside the KRAS exon 2 is referred to as extended RAS testing.
Rearranged During Transfection
The REarranged during Transfection (RET) proto-oncogene encodes a receptor tyrosine kinase growth factor (Regua, 2022). Translocations that result in fusion genes with several partners have been reported, and occur in about 5-10% of thyroid cancer cases (primarily papillary thyroid carcinoma), 1%-2% of non-small-cell lung cancer cases, and occurring in roughly 0.2% colorectal cancers (Thunnissen, 2014; Nagasaka, 2023). RET fusions in breast cancer, occur in less than 1% of cases (Santoro, 2020).
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% to 3.7% (Thunnissen, 2014). Patients with ROS1 fusions are typically never-smokers with adenocarcinoma.
Tumor Mutational Burden
Tumor mutational burden (TMB) is a measure of gene mutations within cancer cells. Initially, assessments of TMB involved whole exome sequencing (WES). More recently, targeted next generation sequencing (NGS) panels are being adapted to estimate TMB. Currently FoundationOne CDx is the only U.S. Food and Drug Administration (FDA) approved panel for estimating TMB, but others are in development. (Merino, 2020).
Tumor Protein p53
Tumor protein p53 (TP53) is a transcription factor protein that binds to DNA and regulates gene expression to prevent alterations of the genome. Accumulating evidence indicates that p53 is the most frequently mutated gene in human cancers and are commonly found in the ovary (47.27%), colon and rectum (44.55%), lung (40.8%), pancreas (38.53%), stomach (36.78%), urethra (35.01%), liver (29.17%), breast (26.44%), prostate (22.52%), bone (16.19%), thyroid (11.13%), hematopoietic and lymphatic (10.13%) and kidney (8.75%) (Wang, 2023; Nishikawa, 2023).
Circulating Tumor DNA
Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or CTCs. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA can be used for genomic characterization of the tumor.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests.
An up-to-date list of FDA cleared or approved companion diagnostics (that includes also includes indications not included in this policy) is available at
https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.
Coding
Effective January 2012, there is a specific CPT code for this testing:
81210 BRAF (v-raf murine sarcoma viral oncogen homolog B1) (e.g., colon cancer), gene analysis, V600E variant.
Additional policies that address NTRK testing:
2022040 Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer
2015002 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)
2022011 Genetic Test: Testing for Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusions
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Policy/ Coverage: |
Effective September 15, 2023, see Policy 2023023 for indications related to immunotherapy and tumor mutational burden testing.
Effective August 2025
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants in tumor tissue of individuals with unresectable or metastatic melanoma, or with resected stage III melanoma to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib) or MEK inhibitors meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria is considered Medically Necessary and is covered.
Testing for BRAF V600E variants in individuals with glioma to select individuals for targeted treatment with dabrafenib in combination with trametinib meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria is considered Medically Necessary and is covered.
Testing for BRAF V600 variants or BRAF fusion rearrangements (e.g., KIAA1549::BRAF) in individuals with relapsed or refractory pediatric low-grade glioma to select individuals for targeted treatment with tovorafenib meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria is considered Medically Necessary and is covered.
Analysis of BRAF V600E variant to predict treatment response to BRAF and MEK-inhibitor combination therapy (e.g., dabrafenib [Tafinlar] and trametinib [Mekinist]) in individuals with BRAF V600E–mutated melanoma meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria is considered Medically Necessary and is covered.
Testing for NTRK gene fusions in individuals with unresectable or metastatic melanoma to select individuals for treatment with FDA-approved kinase inhibitors meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria is considered Medically Necessary and is covered.
Testing for NTRK gene fusions in individuals with glioma to select individuals for treatment with FDA-approved kinase inhibitors meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria is considered Medically Necessary and is covered.
Testing for IDH1 or IDH2 gene variants in individuals with glioma (i.e., grade 2 astrocytoma or oligodendroglioma following surgery including biopsy, sub-total resection, or gross total resection) to select individuals for targeted treatment with vorasidenib meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria is considered Medically Necessary and is covered.
Coverage of testing meets member benefit certificate Primary Coverage Criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants for all other indications in individuals with melanoma not addressed in this or other policies 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, testing for the BRAF V600 variants for all other indications in individuals with melanoma not addressed in this or other policies is considered Not Medically Necessary or is investigational and is not covered. Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for BRAF V600 variants or BRAF fusion rearrangements for all other indications in individuals with glioma not addressed in this or other policies 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, testing for BRAF V600 variants or BRAF fusion rearrangements for all other indications in individuals with glioma not addressed in this or other policies is considered Not Medically Necessary or is investigational and is not covered. Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
Analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma 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, analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma is considered Not Medically Necessary or is investigational and is not covered. Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for NTRK gene fusions for all other individuals with melanoma or glioma to select targeted treatment not addressed in this or other policies 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, testing for NTRK gene fusions for all other individuals with melanoma or glioma to select targeted treatment not addressed in this or other policies is considered Not Medically Necessary or is investigational and is not covered. Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
Testing for IDH1 or IDH2 gene variants for all other individuals with glioma not addressed in this or other policies 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, testing for IDH1 or IDH2 gene variants for all other individuals with glioma not addressed in this or other policies is considered Not Medically Necessary or is investigational and is not covered. Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective August 2024 – July 2025
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants in tumor tissue of individuals with unresectable or metastatic melanoma, or with resected stage III melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib) or MEK inhibitors.
Testing for BRAF V600E variants in individuals with glioma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select individuals for targeted treatment with dabrafenib in combination with trametinib.
Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to BRAF and MEK-inhibitor combination therapy (e.g., dabrafenib [Tafinlar] and trametinib [Mekinist]), in individuals with BRAF V600E–mutated melanoma.
Testing for NTRK gene fusions in individuals with unresectable or metastatic melanoma to select individuals for treatment with FDA-approved kinase inhibitors meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Testing for NTRK gene fusions in individuals with glioma to select individuals for treatment with FDA-approved kinase inhibitors meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants for all other indications in individuals with melanoma not addressed in this or other policies 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, testing for the BRAF V600 variants for all other indications in individuals with melanoma not addressed in this or other policies is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Testing for BRAF V600 variants for all other indications in individuals with glioma not addressed in this or other policies 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, testing for BRAF V600 variants for all other indications in individuals with glioma not addressed in this or other policies is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Testing for NTRK gene fusions for all other individuals with melanoma or glioma to select targeted treatment not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, testing for NTRK gene fusions for all other individuals with melanoma or glioma to select targeted treatment not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective September 15, 2023 – July 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants in tumor tissue of individuals with unresectable or metastatic melanoma, or with resected stage III melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib) or MEK inhibitors.
Testing for BRAF V600E variants in individuals with glioma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select individuals for targeted treatment with dabrafenib in combination with trametinib.
Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to BRAF and MEK-inhibitor combination therapy (e.g., dabrafenib [Tafinlar] and trametinib [Mekinist]), in individuals with BRAF V600E–mutated melanoma.
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants for all other indications in individuals with melanoma not addressed in this or other policies 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, testing for the BRAF V600 variants for all other indications in individuals with melanoma not addressed in this or other policies is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Testing for BRAF V600 variants for all other indications in individuals with glioma not addressed in this or other policies 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, testing for BRAF V600 variants for all other indications in individuals with glioma not addressed in this or other policies is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Effective July 2022– September 14, 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants in tumor tissue of individuals with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib), MEK inhibitors, or immunotherapy.
Testing for BRAF V600 variants in tumor tissue of individuals with resected stage III melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib) or MEK inhibitors.
Analysis of BRAF V600E variant meets member benefit certificate primary coverage criteria to predict treatment response to BRAF and MEK-inhibitor combination therapy (e.g., dabrafenib [Tafinlar] and trametinib [Mekinist]), in individuals with BRAF V600E–mutated melanoma.
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants for all other indications, including but not limited to, use in individuals with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma 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, testing for the BRAF V600 variants for all other indications, including but not limited to, use in individuals with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage
Testing for tumor mutational burden (TMB) in individuals with unresectable or metastatic melanoma or glioma to select individuals for treatment with FDA-approved immunotherapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, testing for tumor mutational burden (TMB) in individuals with unresectable or metastatic melanoma or glioma to select individuals for treatment with FDA-approved immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, analysis of BRAF V600E variant to predict treatment response to all other therapy combinations in individuals with BRAF V600E–mutated melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Effective Prior to July 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants in tumor tissue of patients with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib), MEK inhibitors, or immunotherapy.
Testing for BRAF V600 variants in tumor tissue of patients with resected stage III melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib) or MEK inhibitors.
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma 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, testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage
Testing for tumor mutational burden (TMB) in patients with unresectable or metastatic melanoma or glioma to select patients for treatment with FDA-approved immunotherapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, testing for tumor mutational burden (TMB) in patients with unresectable or metastatic melanoma or glioma to select patients for treatment with FDA-approved immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to November 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants in tumor tissue of patients with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
Testing for BRAF V600 variants in tumor tissue of patients with resected stage III melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma 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, testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to July 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants in tumor tissue of patients with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma 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, testing for the BRAF V600 variants for all other indications, including but not limited to, use in patients with lesser stage melanoma, resectable melanoma, non-melanoma tumors or glioma is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Effective October 2014 - September 2017
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 mutations in tumor tissue of patients with unresectable or metastatic melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 mutations for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors 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, testing for the BRAF V600 mutations for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Effective October 2013- September 2014
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 mutations in tumor tissue of patients with stage IIIC or IV melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with FDA-approved BRAF inhibitors (i.e., vemurafenib, dabrafenib or trametinib).
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Testing for the BRAF V600 mutations for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors 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, testing for the BRAF V600 mutations for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
Effective prior to October 2013
Testing for the BRAF V600E mutation in tumor tissue of patients with stage IIIC or IV melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to select treatment with vemurafenib.
Coverage of testing meets member benefit certificate primary coverage criteria for one test per lifetime.
Testing for the BRAF V600E mutation for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors 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, testing for the BRAF V600E mutation for all other indications, including but not limited to, use in patients with lesser stage melanoma, or with non-melanoma tumors is considered investigational. Investigational services are considered specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Analytic Validity
The analytic validity of a genetic test is its ability to accurately and reliably measure the genotype (or analyte) of interest in the clinical laboratory, and in specimens representative of the population of interest (Teutsch, 2009). Submission to the Office of In Vitro Diagnostics of the FDA for marketing clearance or approval of a diagnostic test requires an extensive demonstration of the analytic validity of the test. Data for cleared or approved tests are summarized in the kit insert (prepared by the manufacturer) and in the Summary of Safety and Effectiveness of the test (prepared by the FDA and publicly available).
The cobas® 4800 BRAF V600 Mutation Test is a real-time polymerase chain reaction (PCR) test intended for the qualitative detection of the BRAFV 600E mutation specifically in DNA that has been extracted from formalin-fixed, paraffin-embedded (FFPE) human melanoma tissue.
Correlation of cobas 4800 BRAF V600 Mutation Test results to Sanger sequencing was tested in the Phase III trial of vemurafenib (Chapman, 2011) on 596 consecutive patients, of which 449 were evaluable. The percent agreement of the BRAF V600 mutation test with Sanger sequencing is shown in the first line of Table 1 when only V600E results were counted as positive. The cobas 4800 BRAF V600 Mutation Test detected 27 V600 mutations (primarily V600K) that were not V600E by Sanger Sequencing. Limited evidence suggests that patients with V600K mutated tumors may also respond to vemurafenib.
Tumor specimens from the patients enrolled in the phase II trial (Ribas, 2011) were also sequenced by Sanger sequencing; specimens that were invalid by Sanger, or that were identified as V600K mutation or as V600 wild type by Sanger were re-sequenced by the more sensitive 454 pyrosequencing method to resolve differences. Correlation to 454 pyrosequencing was 100% if V600K-positive samples were counted as true positives.
Regulatory documents contain additional data detailing the evaluation of analytic sensitivity and specificity, cross reactivity, interference, reproducibility, repeatability, and additional studies of test robustness. In general, correlation with sequencing and extensive analytic validation data support that the test is a sensitive, specific, and robust assay for the detection of the V600E mutation in FFPE melanoma specimens. Patients with V600K mutations will also be identified as positive, although it is not clear that all patients with V600K mutations will be positive. There is very limited evidence that patients with V600K mutations may respond to vemurafenib. Infrequently, patients with V600E2 and V600D mutations may also be detected. Additionally, the method is available as a kit and is partially automated, which should result in wide access and rapid turnaround time relative to the reference standard of sequencing.
Clinical Validity and Utility
The clinical validity of a genetic test is its ability to accurately and reliably predict the clinically defined disorder or phenotype of interest; the clinical utility of a genetic test is the evidence of improved measurable clinical outcomes, and its usefulness and added value to patient management decision-making compared with current management without genetic testing (Teutsch. 2009).
When a treatment is developed for a specific biological target that characterizes only some patients with a particular disease, and a test is co-developed to identify diseased patients with that target, clinical validity and clinical utility studies are no longer separate and sequential. Rather, the clinical studies of treatment benefit, which use the test to select patients, provide evidence of both clinical validity and clinical utility. The primary evidence of clinical validity and utility for the cobas® 4800 BRAF V600 Mutation Test is provided by the Phase III clinical trial of vemurafenib. In addition, evidence from Phase I and Phase II trials is supportive. All trials were enrichment trial designs, in which all patients were positive for a V600 mutation (with a few exceptions in the Phase I trial). The justification for this was both efficiency and possibly potential for harm to patients with BRAF wild type tumors.
Phase III Clinical Trial. This comparative trial, also known as BRIM-3, randomly assigned 675 patients to either vemurafenib (960 mg twice daily orally) or dacarbazine (1,000 mg/m2 body surface area by IV infusion every 3 weeks) to determine whether vemurafenib would prolong the rate of overall or progression-free survival, compared to dacarbazine (Chapman, 2011). All enrolled patients had unresectable, previously untreated stage IIIC or IV melanoma with no active CNS metastases. Melanoma specimens from all patients tested positive for the BRAFV600E mutation on the cobas 4800 BRAF V600 Mutation Test. Included were 19 patients with BRAFV600K mutations and one with a BRAFV600D mutation.
Tumor assessments including CT were performed at baseline, at weeks 6 and 12, and every 9 weeks thereafter. Tumor responses were determined by the investigators according to the RECIST, version 1.1. Primary endpoints were the rate of overall survival and progression-free survival. An interim analysis was planned at 98 deaths and a final analysis at 196 deaths; the published report is the interim analysis, reporting 118 deaths. The median survival had not been reached. Adverse events in the vemurafenib group included grade 2 or 3 photosensitivity skin reactions in 12% of patients, and cutaneous squamous cell carcinoma in 18% of patients. The data and safety monitoring board determined that both co-primary endpoints had met prespecified criteria for statistical significance and recommended that patients in the dacarbazine group be allowed to cross over and receive vemurafenib. The results of this trial comprised the data supporting the efficacy and safety of vemurafenib for submission to the FDA, and established the safety and effectiveness of the cobas 4800 BRAF V600 Mutation Test, resulting in co-approval of drug and companion test.
Phase II Clinical Trial. A Phase II trial, also known as BRIM-2, is currently ongoing at 13 centers. All patients were selected with the cobas 4800 BRAF V600 Mutation Test; 122 cases had BRAFV600E–positive melanoma and 10 cases were positive for BRAFV600K. The early results of this trial have been published only as a meeting abstract and a meeting slide presentation (Robas. 2011). The target overall response rate (primary outcome) was 30%, with a lower boundary of the 95% confidence interval (CI) of at least 20%. At a median follow-up of 10 months, this target was met with an overall response rate of 53% by IRC (95% CI: 44-62%). At 10 months, 27% of patients were still on treatment; the majority of discontinuations were due to disease progression. The most common adverse events of any grade were arthralgias (58%), skin rash (52%), and photosensitivity (52%). The most common grade 3 adverse event was squamous cell carcinoma; these were seen in about 25% of patients, tended to occur in the first 2 months of treatment, and were managed with local excision. There were very few grade 4 adverse events.
Phase I Clinical Trial. The major goals of this trial were to first determine the maximum dose in a dose-escalation phase, then determine the objective response rate and monitor toxicity (Flaherty, 2010). This trial used a PCR assay that was likely a prototype of the final test; only a brief description of the assay was provided in the publication. In the dose-escalation phase, 5 patients with metastatic melanoma tumors who did not have the BRAFV600E mutation received 240 mg or more vemurafenib twice daily (final recommended dose is 960 mg twice daily); of these, none responded. In the extension phase of the trial, 26 of 32 patients with the BRAFV600E mutation responded (81%; 24 partial, 2 complete responses).
Ongoing Clinical Trials
Despite impressive response rates in the Phase I trial, the duration of response to vemurafenib was limited to between 2 and 18 months suggesting the development of resistance; in some patients with BRAFV600E-positive tumors there was no response at all, which was interpreted as primary resistance. Investigations of the mechanisms of resistance have reported evidence of different molecular mechanisms potentially responsible for resistance in different patients (16, 17). It is likely that combined inhibition of BRAF and other key molecular targets, and the use of different combinations in different patients, will be needed in the future. For example, a clinical trial is already underway combining treatment with vemurafenib and a MEK inhibitor in patients who have already been treated with vemurafenib (NCT01271803).
As noted, the BRAF inhibitor dabrafenib is currently in phase II and III clinical trials (NCT01227889; NCT01266967), and is expected to be submitted to the FDA, along with a companion diagnostic test, relatively quickly.
Summary
A large proportion of patients with advanced melanoma have a mutation in the BRAF gene. The Phase III clinical trial of vemurafenib in melanoma patients positive for the BRAFV600E mutation reported a benefit in overall survival and progression-free survival for vemurafenib treatment. These results, which are corroborated by earlier trials, support the clinical validity and clinical utility of the cobas 4800 BRAF V600 Mutation Test, the companion diagnostic test for vemurafenib. Using the test to select patients for treatment results in improved outcomes compared to the usual standard of care, dacarbazine. Thus, this test, and any other tests approved by the FDA to detect the BRAFV600E mutation to select advanced melanoma patients for vemurafenib treatment, may be considered medically necessary.
2012 Update
A literature search conducted through September 2012 did not reveal any new information that would prompt a change in the coverage statement.
2013 Update
Two new BRAF inhibitors received FDA approval since the last policy update. This update contains information relating to these new treatments.
Dabrafenib
The THxID™ BRAF kit is a real-time PCR test intended for the qualitative detection of BRAF V600E and
V600K mutations in DNA samples extracted from formalin-fixed paraffin-embedded (FFPE) human melanoma tissue (FDA, 2013). Two oligonucleotide probes labeled with different fluorescent dyes (one for internal controls and the other for mutation sequence alleles) are measured at characteristic wavelengths and compared by an autoanalyzer. Results are reported as either “mutation(s) detected” or “mutation(s) not detected” (or “invalid,” which requires troubleshooting and a repeat of the test). The threshold of detection, defined as the smallest proportion of mutated alleles for which the assay yields a positive result in 95% of tests, is 5% for
V600E and V600K mutations.
Correlation of the THxID BRAF assay with Sanger sequencing was tested in 898 consecutive clinical trial samples. Forty-three samples (5%) were invalid or quantity not sufficient. Excluding these samples, there were 35 discordant cases (4%). The THxID BRAF kit detected as V600E mutation-positive 2 samples determined by Sanger sequencing to be
V600D mutation-positive.
One Phase III randomized, controlled, open-label trial of dabrafenib for advanced (stage IV or unresectable stage III) melanoma has been published (Hauschild, 2012); the results of this trial are summarized in Table 3. The main objective of this RCT was to study the efficacy of dabrafenib vs. standard dacarbazine treatment in patients selected to have
BRAF V600E mutated metastatic melanoma. Two-hundred-fifty patients were randomized 3:1 to receive oral dabrafenib 150 mg twice daily versus intravenous dacarbazine 1,000 mg/m2 every 3 weeks. The primary outcome was progression-free survival (PFS), and secondary outcomes were overall survival, objective response rate, and adverse events.
Median progression-free survival for the dabrafenib and dacarbazine groups was 5.1 months and 2.7 months, respectively. Overall survival did not differ significantly between groups; 11% of patients in the dabrafenib group died compared to 14% in the dacarbazine group (hazard ratio: 0.61, 95% CI: 0.25–1.48). However, 28 patients (44%) in the dacarbazine arm crossed over at disease progression to receive dabrafenib. The objective response rate, defined as complete plus partial responses, was greater in the dabrafenib group (50%, 95% CI: 42.4–57.1%) compared to the dacarbazine group (6%, 95% CI: 1.8–15.5%). Treatment-related adverse events grade 2 or higher occurred in 53% of patients who received dabrafenib and in 44% of patients who received dacarbazine. Grade 3-4 adverse events were uncommon in both groups. The most common serious adverse events were cutaneous squamous cell carcinoma (7% vs. none in controls); serious non-infectious, febrile drug reactions (3% grade 3 pyrexia vs. none in controls); and severe hyperglycemia (>250-500 mg/dL), requiring medical management in non-diabetic patients or change in management of diabetic patients (6% vs. none in controls). Results demonstrated that targeting dabrafenib against
BRAF V600E mutated melanoma results in a benefit in progression-free survival. Patients were allowed to cross over at the time of progression, and the effect of dabrafenib on overall survival was favorable but not statistically significant.
All tissue specimens from patients screened for enrollment in the clinical trial were analyzed centrally by a clinical trial assay. Outcomes were linked retrospectively to BRAF testing by the THxID BRAF kit. Of 250 patients enrolled in the trial, specimens from 237 patients (177 [95%] in the dabrafenib arm and 55 [87%] in the dacarbazine arm) were retested with the THxID BRAF kit. Reanalysis of the primary end point, PFS, in patients who were V600E positive by the THxID BRAF kit showed a treatment effect that was nearly identical to the overall result by central assay. Additional analysis for discordant results assumed a worst case scenario, i.e., a hazard ratio of 1 for patients
V600E-mutation-positive by the THxID BRAF test but mutation negative by central assay. The hazard ratio was 0.34 (95% CI: 0.23–0.50) (FDA, 2013).
Trametinib.
The clinical efficacy and safety of trametinib was assessed in the Phase III, open-label METRIC trial (Flaherty, 2012). Patients with stage IV or unresectable stage IIIC cutaneous melanoma were randomized 2:1 to receive trametinib 2 mg orally once daily (n=214) or chemotherapy (n=108), either dacarbazine 1,000 mg/m2 IV every 3 weeks or paclitaxel 175 mg/m2 IV every 3 weeks at investigator discretion. Most patients (67%) were previously untreated. The primary efficacy endpoint was PFS; secondary endpoints included overall survival, overall response rate, and safety. Tumor assessments were performed at baseline and at weeks 6, 12, 21, and 30 and then every 12 weeks.
Median PFS was 4.8 months (95% CI: 4.3–4.9) in the trametinib arm and 1.5 months (95% CI: 1.4-2.7) in the chemotherapy arm, a statistically significant difference. (Table 3) Although median overall survival had not been reached at the time of the report publication, 6-month survival was statistically longer in the trametinib group than in the chemotherapy group (p=0.01); 51 of 108 patients (47%) in the chemotherapy group crossed over at disease progression to receive trametinib. In the trametinib and chemotherapy groups, adverse events led to dose interruption in 35% and 22% of patients, respectively, and to dose reduction in 27% and 10% of patients, respectively. Decreased ejection fraction or ventricular dysfunction was observed in 14 patients (7%) in the trametinib group; 2 patients had grade 3 cardiac events that led to permanent drug discontinuation. Twelve percent of the trametinib group and 3% of the chemotherapy grouped experienced grade 3 hypertension. Nine percent of patients in the trametinib group experienced ocular events (mostly grade 1 or 2), most commonly blurred vision (4%). The most common adverse events in the trametinib group were rash, diarrhea, peripheral edema, and fatigue; rash was grade 3 or 4 in 16 patients (8%). Cutaneous squamous cell carcinoma was not observed during treatment.
Tumor tissue was evaluated for BRAF mutations at a central site using a clinical trial assay. Retrospective THxID BRAF analysis was conducted on tumor samples from 289 patients (196 [92%] in the trametinib arm and 93 [86%] in the chemotherapy arm). Reanalysis of PFS in patients who were V600E or
V600K-positive by the THxID BRAF kit showed a treatment effect that was almost identical to the overall result by central assay. Additional analysis for discordant results assuming a worst case scenario as above yielded a hazard ratio of 0.48 (95% CI: 0.35–0.63) (FDA, 2013).
Resistance to BRAF inhibitors
Median duration of response in the Phase I (extension), II, and III studies of vemurafenib was approximately 6 months, 6.7 months, and 5.5 months, respectively, suggesting the development of resistance; (Chapman, 2011; Sosman, 2012; Flaherty, 2010) in some patients with BRAFV600E-positive tumors, there was no response at all, which was interpreted as primary resistance. Investigations of the mechanisms of resistance have reported evidence of different molecular mechanisms potentially responsible for resistance in different patients (Johannessen, 2010; Nazarian, 2010). It is likely that combined inhibition of BRAF and other key molecular targets, and the use of different combinations in different patients, will be needed in the future. For example, MEK proteins are also components of the MAP kinase signal-transduction pathway; like BRAF inhibitors, MEK inhibitors, such as trametinib, have been designed to interfere with this pathway and may be used in combination. An open-label Phase I/II trial examined the pharmacokinetics, safety, and efficacy of dabrafenib plus trametinib combination therapy in 247 patients with metastatic (stage IV) melanoma and
BRAF V600E or V600K mutations (Flaherty, 2012). Maximum tolerated combination dosing was not reached. One dose-limiting toxic effect, recurrent neutrophilic panniculitis, occurred in 24 patients who received the highest dose level (dabrafenib 150 mg twice daily plus trametinib 2 mg daily), and this was the recommended dose for efficacy testing. Median PFS, the primary efficacy endpoint, was 9.4 months in the combination therapy group (n=54) and 5.8 months in the dabrafenib (150 mg twice daily) monotherapy group (n=54; hazard ratio 0.39, 95% CI: 0.25–0.62; p<0.001). Complete or partial response occurred in 76% of patients in the combination therapy group and 54% of the monotherapy group (p=0.03). Median duration of response was 10.5 (95% CI: 7.4–14.9) months and 5.6 months (95% CI: 4.5–7.4), respectively. Cutaneous squamous cell carcinoma occurred in 7% of the combination therapy group and 19% of the monotherapy group (p=0.09). Fever was more common in the combination therapy group (71% vs. 26% monotherapy; p=<0.001). Other trials of vemurafenib, dabrafenib, and trametinib in combination with each other and with other treatments (e.g., high-dose interleukin-2) are currently in progress, as listed below.
Ongoing Clinical Trials
A search of the ClinicalTrials.gov website identified a number of ongoing Phase III trials of BRAF inhibitor therapy in melanoma. Most trials study combination therapy. All trials are in patients with unresectable stage III or stage IV melanoma, except for NCT01667419 under “Single agents” and NCT01682083 under “Combination treatments,” which are in patients with completely resected melanoma.
Currently active Phase III trials of BRAF inhibitor therapy for melanoma:
Summary
A large proportion of patients with advanced melanoma have a mutation in the
BRAF gene. There are 2 Phase III randomized controlled trials (RCTs) of BRAF inhibitors (vemurafenib and dabrafenib) in advanced melanoma patients who are positive for the
BRAFV600E mutation and 1 Phase III trial of a MEK inhibitor (trametinib) in advanced melanoma patients who are positive for
BRAF V600E or V600K mutations. All of the trials reported a benefit in progression-free survival for treatment with a BRAF inhibitor. In addition, the vemurafenib and trametinib trials reported a significant improvement in overall mortality; the dabrafenib trial did not demonstrate a difference in overall survival. These results support the clinical validity and clinical utility of the cobas 4800 BRAF V600 Mutation Test to select patients for treatment with vemurafenib, and the THxID BRAF kit to select patients for treatment with dabrafenib and trametinib.
2016 Update
A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Combination BRAF (Dabrafenib) and MEK (Trametinib) Inhibition
Efficacy of combination treatment with dabrafenib and trametinib has been established with 2 phase 3 clinical trials (Long, 2015; Robert, 2015; Long, 2014; NCCN, 2016).
Clinical efficacy of combination treatment with dabrafenib and trametinib was evaluated in the phase 3 open-label by Long and colleagues (Long, 2015; Long 2014). In this study, 4234 patients with unresectable stage IIC or stage IV melanoma with a BRAF V600E or V600K mutation were randomized to either a combination of dabrafenib and trametinib or dabrafenib and placebo. The primary end point was progression-free survival, reported in a first publication followed by a second publication in which longer term overall survival was reported (Long, 2015).
Median PFS was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group. The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenibonly group. An interim overall survival analysis showed a difference in survival which was statistically significant with standard statistical criteria, but did not cross the prespecified stopping boundary. The rate of cutaneous squamous cell carcinoma was lower in the dabrafenib-trametinib group (2% vs 9%), whereas pyrexia occurred in more patients (51% vs 28%). In the longer term study assessing overall survival, median survival was 25.1 months in the dabrafenib-trametinib group versus 18.7 months in the dabrafenib-only group.
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
This update focuses on the use of testing for
BRAF pathogenic variants in individuals with glioma.
Analytic Validity
Currently there is no standard method for testing
BRAF status in neuropathology. DNA-based tests for melanomas and IHC are used. The analytic validity of these methods is described in the previous section on melanoma.
Clinical Validity and Clinical Utility
Sorafenib is a multikinase inhibitor with potent in vitro activity against both
BRAF wild-type and V600E variant as well as vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), and
c-KIT. Several phase 2 single-arm prospective studies have investigated the use of sorafenib in newly diagnosed and recurrent, adult and pediatric, low- and high-grade gliomas in various combinations with other treatments. Results have not shown sorafenib to be effective. Most studies did not report BRAF V600 variant status.
Hyman et al (2015) published results of a multicenter phase 2 “basket” study of vemurafenib in
BRAF V600 variant–positive nonmelanoma cancers (Hyman, 2015).
A total of 122 patients with BRAF V600 pathogenic variants were enrolled, including 8 patients with gliomas. Response was assessed by site investigators using RECIST criteria. Of the 8 glioma patients, 2 died before the 1-month evaluation; 4 had stable disease at 12, 6, 4, and 3 months and 2 had progressive disease at 2 and 7 months, all respectively.
Studies of sorafenib in patients with newly diagnosed and recurrent gliomas combined with various other treatments have not shown benefit, although most did not report
BRAF V600 status. Evaluation of the BRAF and MEK inhibitors vemurafenib, dabrafenib, and trametinib in patients with gliomas has been limited to 1 phase 2 “basket” study (including 8 patients with glioma), case reports, and small case series. Several early phase studies are ongoing.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2018. The key identified literature is summarized below.
Vemurafenib
The primary evidence of clinical validity and utility for the cobas 4800 BRAF V600 Mutation Test is provided by the phase 3 clinical trial of vemurafenib that enrolled patients testing positive for a V600 variant.
The BRIM-3 trial as reported by Chapman et al (2011) randomized a total of 675 patients to vemurafenib (960 mg twice daily orally) or to dacarbazine (1000 mg/m2 body surface area by intravenous infusion every 3 weeks) to determine whether vemurafenib would prolong the rate of OS or PFS compared with dacarbazine (Chapman, 2011). All enrolled patients had unresectable, previously untreated stage IIIC or IV melanoma with no active central nervous system metastases. Melanoma specimens from all patients tested positive for the BRAF V600E variant on the cobas 4800 BRAF V600 Mutation Test. Included were 19 patients with
BRAF V600K variants and 1 with a BRAF V600D variant.
Tumor assessments, including computed tomography, were performed at baseline, at weeks 6 and 12, and every 9 weeks after that. Tumor responses were determined by investigators using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Primary end points were the rate of OS and PFS. An interim analysis was planned at 98 deaths and a final analysis at 196 deaths; the published report is the interim analysis. The data and safety monitoring board determined that both coprimary end points had met prespecified stopping criteria and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib. At the time the trial was halted, 118 patients had died; median survival had not been reached. Results for OS strongly favored vemurafenib, with a hazard ratio (HR) of 0.37 (95% confidence interval [CI], 0.26 to 0.55). Adverse events in the vemurafenib group included grade 2 or 3 photosensitivity skin reactions in 12% of patients and cutaneous squamous cell carcinoma in 18%. The results of this trial comprised the efficacy and safety data supporting vemurafenib submission to FDA and established safety and effectiveness of the cobas 4800 BRAF V600 Mutation Test, resulting in coapproval of both the drug and companion test.
In 2017, final OS results from BRIM-3 were reported by Chapman et al (Chapman, 2017). Eighty-four (25%) of the 338 dacarbazine patients crossed over to vemurafenib and overall 173 (51%) of the 338 patients in the dacarbazine group and 175 of the 337 patients (52%) in the vemurafenib group received subsequent anticancer therapies, most commonly ipilimumab. Median OS without censoring at crossover was 13.6 months (95% CI, 12.0 to 15.4) in vemurafenib vs 10.3 months (95% CI, 9.1 to 12.8 months) in dacarbazine (HR=0.81; 95% CI, 0.68 to 0.96); p=0.01).
Combination BRAF Plus MEK Inhibitors
Dabrafenib and Trametinib
The efficacy of combination dabrafenib plus trametinib treatment has been established with two phase 3 clinical trials (Long, 2015; Robert, 2015; Long, 2014). This combination agent was evaluated in the phase 3 open-label trial by Long et al (Long, 2014; Long 2015). In this trial, 4234 patients with unresectable stage IIC or stage IV melanoma with a BRAF V600E or V600K variant were randomized to dabrafenib plus trametinib or dabrafenib plus placebo. The primary end point was PFS, as reported in a first publication, followed by a second publication in which longer term OS was reported (Long, 2014; Long, 2015).
Median PFS was 11.0 months in the dabrafenib plus trametinib group and 8.8 months in the dabrafenib-only group. The overall response rate was 67% in the dabrafenib plus trametinib group and 51% in the dabrafenib-only group. An interim OS analysis showed a statistically significant difference using standard statistical criteria, but the difference did not cross the prespecified stopping boundary. The rate of cutaneous squamous cell carcinoma was lower in the dabrafenib plus trametinib group (2% vs 9%), whereas pyrexia occurred in more patients (51% vs 28%). In the longer term study assessing OS, median survival was 25.1 months in the dabrafenib plus trametinib group and 18.7 months in the dabrafenib-only group.
Encorafenib Plus Binimetinib
Dummer et al reported on results of a phase 3 COLUMBUS RCT comparing encorafenib, a BRAF inhibitor, alone or in combination with the MEK inhibitor binimetinib, with vemurafenib in patients who had advanced
BRAF V600-variant unresectable or metastatic melanoma (Dummer, 2018). The COLUMBUS trial was conducted in 162 hospitals in 28 countries between 2013 and 2015; patients were randomized (1:1:1) to oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (n=192), oral encorafenib 300 mg once daily (n=194), or oral vemurafenib 960 mg twice daily (n=191). The primary outcome was PFS for encorafenib plus binimetinib vs vemurafenib. Analyses were done on the intention-to-treat population. Median follow-up was 17 months. PFS was significantly increased with encorafenib plus binimetinib compared with vemurafenib (median PFS=14.9 months vs 7.3 months in the vemurafenib group; HR=0.54; 95% CI, 0.41 to 0.71; p<0.001; see Table 2). OS was not reported. The most common grade 3 or 4 adverse events were increased γ-glutamyltransferase (9%), increased creatine phosphokinase (7%), and hypertension (6%) in the encorafenib plus binimetinib group; palmoplantar erythrodysesthesia syndrome (14%), myalgia (10%), and arthralgia (9%) in the encorafenib group; and arthralgia (6%) in the vemurafenib group.
Clinically Valid and Clinical Usefulness
Two RCTs of BRAF and/or MEK inhibitors in patients with resected stage III
BRAF-variant melanoma, have been reported by Long et al in 2017 and Maio et al in 2018.
Long et al reported on results of COMBI-AD, a phase 3 RCT comparing adjuvant combination therapy using dabrafenib plus trametinib with placebo in 870 patients who had stage III melanoma with
BRAF V600E or V600K variants (Long, 2017). In 2013 and 2014 when patients were being enrolled in COMBI-AD, observation was the standard of care after resection of stage III melanoma in most countries. With a median follow-up of 2.8 years, the 3-year rate of relapse-free survival was 58% in the combination group and 39% in the placebo group (HR=0.47; 95% CI, 0.39 to 0.58; p<0.001). OS rates at 3 years were 86% and 77%, respectively (HR=0.57; 95% CI, 0.42 to 0.79; p<0.001).
Maio et al reported on results of BRIM8, a phase 3 RCT comparing adjuvant vemurafenib monotherapy with placebo in 498 patients who had stage IIC, IIIA, IIIB, or IIIC
BRAF V600 variant-positive melanoma (Maio, 2018). Patients with stage IIC, IIIA, or IIIB disease were enrolled in cohort 1 (n=314), and patients with stage IIIC disease were enrolled in cohort 2 (n=184). As stated previously, during enrollment, observation was standard care for stage III melanoma. A hierarchical testing strategy was prespecified for the primary outcome (disease-free survival) based on the assumption that observing a biologic effect in higher risk disease (ie, cohort 2) would suggest a treatment effect across the continuum of melanoma given the effect is already established in metastatic melanoma. In the hierarchical strategy, only a p value of 0.05 or less in cohort 2 would allow for results in cohort 1 to be considered significant. The median trial follow-up was 34 months (interquartile range, 26-42 months) in cohort 2 and 31 months (interquartile range, 26-41 months) in cohort 1. In cohort 2, median disease-free survival was 23 months (95% CI, 19 to 27 months) in the vemurafenib group and 15 months (95% CI, 11 to 36 months) in the placebo group (HR=0.80; 95% CI, 0.54 to 1.18; p=0.26). In cohort 1, median disease-free survival was not reached (95% CI, not estimable) in the vemurafenib group and 37 months (95% CI, 21 to not estimable) in the placebo group (HR=0.54; 95% CI, 0.37 to 0.78); however, this result cannot be considered statistically significant because of the prespecified hierarchical testing strategy.
In summary, RCTs of BRAF and MEK inhibitor therapy in stage III melanoma patients selected by
BRAF V600 variant testing have shown reductions in recurrence risk. One well-conducted RCT of combination BRAF and MEK inhibitor treatment with dabrafenib plus trametinib has shown superiority for recurrence risk and OS in
BRAF variant-positive, stage III patients compared with placebo. Single-agent BRAF inhibitor treatment using vemurafenib compared with placebo showed numeric benefit for disease-free survival in patients with stage IIC, IIIA, or IIIB BRAF V600 variant-positive melanoma but this result must be considered exploratory given the lack of statistically significant benefit in stage IIIC disease and the hierarchical statistical testing strategy. There are no RCTs directly comparing BRAF and MEK inhibitor therapy with immunotherapy as an adjuvant treatment for stage III patients with
BRAF pathogenic variants.
2019 Update
A literature search was conducted through June 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Ascierto et al published long-term outcomes from the COLUMBUS trial (Ascierto, 2020). The median follow-up for OS was 48.8 months. Compared with vemurafenib, the combination of encorafenib plus binimetinib significantly reduced the risk of death by 39% (HR, 0.61; 95% CI, 0.48 to 0.79) and increased the duration of PFS (HR, 0.51; 95% CI, 0.39 to 0.67). The OS rates at 3 years were 47%, 41%, and 31% for encorafenib plus binimetinib, encorafenib, and vemurafenib groups, respectively. All subgroup analyses favored combination treatment with encorafenib plus binimetinib versus treatment with vemurafenib alone.
Gutzmer et al reported primary results from IMspire150, a phase 3, double-blind RCT of atezolizumab, vemurafenib, and cobimetinib (n=256) compared to placebo, vemurafenib, and cobimetinib (n=258) as first-line treatment for unresectable advanced BRAF V600-positive melanoma (Gutzmer, 2020). The primary endpoint was investigator-assessed PFS. The median follow-up in the overall study population was 18.9 months. At data cut-off, 327 patients had progressive disease by investigator assessment or had died, including 148 (58%) of patients in the atezolizumab group and 179 (69%) in the control group. The atezolizumab with vemurafenib and cobimetinib group experienced a median PFS per investigator assessment of 15.1 months (95% CI, 0.63 to 0.97) compared to 10.6 months (95% CI, 9.3 to 12.7) in the control group. A 77% concordance rate for progressive disease assessment by study investigators versus independent review committee was reported. The primary reason for discordant results (n=109) was the assessment of progressive disease per study investigators but not the independent review committee. The prevalence of treatment-related adverse events was comparable between the 2 groups. PD-L1 expression status was not significantly associated with the treatment effect.
Marabelle et al reported the association of TMB-high (TMB-H) status to response to pembrolizumab in patients with various previously treated unresectable or metastatic solid tumors enrolled in a prespecified exploratory analysis of the nonrandomized, phase 2 KEYNOTE-158 study (NCT02628067) (Marabelle, 2020). TMB-H was defined as
≥10 mutations per megabase according to the FoundationOne CDx panel. The proportion of patients with an objective response in the TMB-H group was 29%. At a median follow-up of approximately 3 years, the median duration of response was not reached in the TMB-H group and was 33.1 months in the non-TMB-H group. TMB-H status was associated with improved response irrespective of PD-L1 status. Median PFS and OS did not differ between the high and non-high TMB groups. Objective responses were observed in 24 (35%; 95% CI, 24 to 48) of 68 participants who had both TMB-H status and PD-L1-positive tumours (ie, PD-L1 combined positive score of
≥1) and in 6 (21%; 8 to 40) of 29 participants who had TMB-H status and PD-L1-negative tumors.
Notably, patients with melanoma or glioma were not included in these analyses. Study eligible cancers were limited to anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar. The prescribing information for pembrolizumab includes a “Limitation of Use” stating that the safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Several early phase "basket" studies, case reports, and small case series have suggested clinical benefit with vemurafenib, dabrafenib, and trametinib in patients with glioma and
BRAF V600 pathogenic variants (Hyman, 2015; Kaley, 2018; Brown, 2017; Marks, 2018; Wen, 2022). Ongoing phase 3 studies of targeted therapy with these agents were not identified.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma (v.2.2023) include the following recommendations on somatic genetic testing relevant to this policy (NCCN, 2023):
NCCN guidelines on central nervous system cancers (v.1.2023) include the following recommendation on somatic genetic testing in glioma relevant to this policy (NCCN, 2023):
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2024. No new literature was identified that would prompt a change in the coverage statement.
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2025. No new literature was identified that would prompt a change in the coverage statement.
2026 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2026. No new literature was identified that would prompt a change in the coverage statement.
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American Cancer Society.(2011) Melanoma Skin Cancer. http://www.cancer.org/Cancer/SkinCancer-Melanoma/DetailedGuide/melanoma-skin-cancer-key-statistics. Last accessed September 12, 2011.
Anderson S, Bloom KJ, Vallera DU et al.(2012) Multisite Analytic Performance Studies of a Real-Time Polymerase Chain Reaction Assay for the Detection of BRAF V600E Mutations in Formalin-Fixed, Paraffin-Embedded Tissue Specimens of Malignant Melanoma. Arch Pathol Lab Med 2012; 136(11):1385-91. Ascierto PA, Dummer R, Gogas HJ, et al.(2020) Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer. Feb 2020; 126: 33-44. PMID 31901705 Ascierto PA, McArthur GA, Dréno B, et al.(2016) Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutantmelanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. Sep 2016;17(9): 1248-60. PMID 27480103 Brown NF, Carter T, Kitchen N, et al.(2017) Dabrafenib and trametinib in BRAFV600E mutated glioma. CNS Oncol. Oct 2017; 6(4): 291-296. PMID 28984141 Burotto M, Zvirbule Z, Mochalova A, et al.(2023) IMscin001 Part 2: a randomised ph III, open-label, multicentre st exam pharmacokinetics, eff, immunogenicity, safe of atezolizumab sub versus intraven admin in prev treated locally adv or met non-small-cell lung can and pharm comp with other appr ind. Ann Oncol. Aug 2023; 34(8): 693-702. PMID 37268157 Center For Drug Evaluation and Research.(2011) Summary review for vemurafenib. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429Orig1s000SumR.pdf Last accessed September 12, 2011. Chapman PB, Hauschild A, Robert C et al.(2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26):2507-16. Chapman PB, Hauschild A, Robert C, et al.(2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. Chapman PB, Robert C, Larkin J, et al.(2017) Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann Oncol. Oct 1 2017;28(10):2581-2587. PMID 28961848 ClinicalTrials.gov (2023).(2023) Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Pediatric PatientsWith BRAF V600 Mutation Positive LGG or Relapsed or Refractory HGG Tumors: Study Results. https://clinicaltrials.gov/ct2/show/results/NCT02684058?term=NCT02684058&draw=2&rank=1. Accessed May 30, 2023. Dummer R, Ascierto PA, Gogas HJ, et al.(2018) Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. May 2018;19(5):603-615. PMID 29573941 Dummer R, Flaherty KT, Robert C, et al.(2022) COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma. J ClinOncol. Dec 20 2022; 40(36): 4178-4188. PMID 35862871 Dummer R, Goldinger SM, Turtschi CP, et al.(2014) Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. Feb 2014; 50(3): 611-21. PMID 24295639 FDA. Companion diagnostic devices: in vitro and imaging tools. Available online at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Last accessed September 2013. FDA. Companion diagnostic devices: in vitro and imaging tools. Available online at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Last accessed September 2013. FDA. Draft guidance for industry and food and drug administration staff: in vitro companion diagnostic devices. Available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm262292.htm. FDA. Draft guidance for industry and food and drug administration staff: in vitro companion diagnostic devices. July 14, 2011. Available online at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm262292.htm. Last accessed September 2013. FDA. THxID™-BRAF kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument - P120014. BioMérieux labeling, May 2013. Available online at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=p120014. Last accessed September 2013. Flaherty KT, Infante JR, Daud A et al.(2012) Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med 2012; 367(18):1694-703. Flaherty KT, Puzanov I, Kim KB, et al.(2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19. Flaherty KT, Robert C, Hersey P et al.(2012) Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. N Engl J Med 2012; 367(2):107-14. Flaherty KT.(2010) Narrative Review: BRAF opens the door to therapeutic advances in melanoma. Ann Intern Med. 2010;153:587-591. Food and Drug Administration (FDA).(2023) Center for Drug Evaluation and Research (CDER). NDA/BLA Multi-disciplinary Review and Evaluation (NDA 218213): Repotrectinib (BMS-986472). 2023; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/218213Orig1s000MultidisciplineR.pdf. Accessed May 26, 2025. Food and Drug Administration (FDA).(2024) Center for Drug Evaluation and Research (CBER).NDA/BLA Muti-disciplinary Review and Evaluation: NDA 217700 and 218033: Tovorafenib (DAY101). 2024; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217700Orig1s000,%20218033Orig1s000MultidisciplineR.pdf. Accessed May 25, 2025. Food and Drug Administration.(2017) SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED): FoundationOne CDx™. https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019B.pdf. Accessed April 26, 2018. Genentech, Inc. Zelboraf® (vemurafenib) tablet prescribing information, July 2013. Available online at: http://www.zelboraf.com/. Last accessed September 2013. Genentech, Inc. Zelboraf® (vemurafenib) tablet prescribing information, July 2013. Available online at: http://www.zelboraf.com/. Last accessed September 2013. GlaxoSmithKline. Mekinist (trametinib) tablets prescribing information, May 2013. Available online at: http://www.mekinist.com/. Last accessed September 2013. GlaxoSmithKline. Tafinlar (dabrafenib) capsules prescribing information, May 2013. Available online at: http://www.tafinlar.com/. Last accessed September 2013. Gogas HJ, Kirkwood JM, Sondak VK.(2007) Chemotherapy for metastatic melanoma: time for a change? Cancer 2007; 109(3):455-64. Gutzmer R, Stroyakovskiy D, Gogas H, et al.(2020) Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF V600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Jun 13 2020; 395(10240): 1835-1844. PMID 32534646 Hauschild A, Grob JJ, Demidov LV et al.(2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380(9839):358-65. Hyman DM, Puzanov I, Subbiah V, et al.(2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. Aug 20 2015;373(8):726-736. PMID 26287849 Johannessen CM, Boehm JS, Kim SY et al.(2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468(7326):968-72. Joseph EW, Pratilas CA, Poulikakos PI et al.(2010) The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A 2010; 107(33):14903-8. Kaley T, Touat M, Subbiah V, et al.(2018) BRAF Inhibition in BRAF V600 -Mutant Gliomas: Results From the VE-BASKET Study. J Clin Oncol. Dec 10 2018; 36(35): 3477-3484. PMID 30351999 Kilburn LB, Khuong-Quang DA, Hansford JR, et al.(2024) The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med. Jan 2024; 30(1): 207-217. PMID 37978284 King AJ, Patrick DR, Batorsky RS et al.(2006) Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res 2006; 66(23):11100-5. Cancer Res 2006; 66(23):11100-5. Label information for ipilimumab.(2011) Center For Drug Evaluation and Research. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf. Last accessed September 12, 2011. Long GV, Hauschild A, Santinami M, et al.(2017) Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. Nov 9 2017;377(19):1813-1823. PMID 28891408 Long GV, Stroyakovskiy D, Gogas H, et al.(2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. Nov 13 2014;371(20):1877-1888. PMID 25265492 Long GV, Stroyakovskiy D, Gogas H, et al.(2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. Aug 1 2015;386(9992):444-451. PMID 26037941 Long GV, Stroyakovskiy D, Gogas H, et al.(2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. Aug 1 2015;386(9992):444-451. PMID 26037941 Long GV, Trefzer U, Davies MA, et al.(2012) Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. Nov 2012; 13(11): 1087-95. PMID 23051966 Louis DN, Ohgaki H, Wiestler HOD, et al.(2016) WHO Classification of Tumours of the Central Nervous System. Revised. 4th ed. Lyon: WHO Press; 2016. Louis DN, Perry A, Wesseling P, et al.(2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. Aug 02 2021; 23(8): 1231-1251. PMID 34185076 Maio M, Lewis K, Demidov L, et al.(2018) Adjuvant vemurafenib in resected, BRAF(V600) mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. Apr 2018;19(4):510-520. PMID 29477665 Marabelle A, Le DT, Ascierto PA, et al.(2020) Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. Jan 01 2020; 38(1): 1-10. PMID 31682550 Marks AM, Bindra RS, DiLuna ML, et al.(2018) Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib. Pediatr Blood Cancer. May 2018; 65(5): e26969. PMID 29380516 Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al.(2023) Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med. Aug 17 2023; 389(7): 589-601. PMID 37272516 Merino DM, McShane LM, Fabrizio D, et al.(2020) Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer. Mar 2020; 8(1). PMID 32217756 National Comprehensive Cancer Network (NCCN).(2016) Clinical Practic Guidelines in Oncology, Melanoma v1.2016. http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Central Nervous System Cancers. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf.Accessed May 30, 2023. National Comprehensive Cancer Network (NCCN).(2023) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Cutaneous Melanoma. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf.Accessed May 29, 2023. National Comprehensive Cancer Network (NCCN).(2025) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Central Nervous System Cancers. Version 5.2024. March 18, 2025; https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed May 19, 2025. National Comprehensive Cancer Network (NCCN).(2025) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Cutaneous Melanoma. Version 2.2025. January 28, 2025; https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed May 20, 2025. National Comprehensive Cancer Network (NCCN).(2025) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Pediatric Central Nervous System Cancers. Version 2.2025. January 17, 2025; https://www.nccn.org/professionals/physician_gls/pdf/ped_cns.pdf. Accessed May 21, 2025. Nazarian R, Shi H, Wang Q et al.(2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010; 468(7326):973-7. Ribas A, Kim KB, Schuchter LM et al. Ribas A, Kim KB, Schuchter LM et al.(2011) BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. J Clin Oncol 2011; 29 (Suppl):Abstract 8509. Robert C, Karaszewska B, Schachter J, et al.(2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. Jan 1 2015;372(1):30-39. PMID 25399551 Rubinstein JC, Sznol M, Pavlick AC et al.(2010) Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med 2010; 8:67. Sondergaard JN, Nazarian R, Wang Q et al.(2010) Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med 2010; 8:39. Stransky N, Cerami E, Schalm S, et al.(2014) The landscape of kinase fusions in cancer. Nat Commun. Sep 10 2014; 5: 4846. PMID 25204415 Takle AK, Brown MJ, Davies S et al.(2006) The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett 2006; 16(2):378-81. Teutsch SM, Bradley LA, Palomaki GE et al.(2009) The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med 2009; 11(1):3-14. TRK Fusion Cancer.(2025) TRK Fusion Cancer (Testing). https://trkcancer.com/testing. Accessed May 19, 2025. Vultur A, Villanueva J, Herlyn M.(2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clin Cancer Res. 2011 Apr 1;17(7):1658-1663. Vultur A, Villanueva J, Herlyn M.(2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Nature 2010; 467(7315):596-9. Wen PY, Stein A, van den Bent M, et al.(2022) Dabrafenib plus trametinib in patients with BRAF V600E -mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. Jan 2022; 23(1): 53-64. PMID 34838156 Yang H, Higgins B, Kolinsky K et al.(2010) RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 2010; 70(13):5518-27. |
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