Clinical Policy Title: Molecular analysis for targeted therapy of non-small cell lung cancer

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1 Clinical Policy Title: Molecular analysis for targeted therapy of non-small cell lung cancer Clinical Policy Number: Effective Date: April 1, 2016 Initial Review Date: January 20, 2016 Most Recent Review Date: January 11, 2018 Next Review Date: January 2019 Related policies: Policy contains: Anaplastic Lymphoma Kinase. Epidermal Growth Factor Receptor. Non-small cell lung cancer. ROS1 mutations. Targeted therapy. CP# CP# CP# CP# CP# CP# CP# CP# CP# CP# CP# CP# CP# CP# CP# CP# CP# Advanced non-small cell lung cancer with TKI and PD-1 drugs Familial polyposis gene testing Gene expression profile testing for breast cancer Genetic testing for Alzheimer s disease Genetic testing for autism spectrum disorders Genetic testing for breast and ovarian cancer Genetic testing for cystic fibrosis Genetic testing for cytochrome p450 Polymorphisms Genetic testing for Duchenne muscular dystrophy Genetic testing for G1691A Polymorphisms Factor V Leiden Genetic testing for hereditary cancer susceptibility Genetic testing for hereditary cardiomyopathy Genetic testing for long QT syndrome (LQTS) Genetic testing for rare diseases Genetic testing for prostate cancer prognosis Genomic testing in neurology Genomic testing in sensorineural hearing loss ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peerreviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and reg1.ulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. 1

2 Coverage policy Select Health of South Carolina considers the use of molecular analysis for targeted therapy of advanced non-small cell lung cancer (NSCLC) to be clinically proven and, therefore, medically necessary, under certain conditions. Analysis of two types of somatic mutations within the epidermal growth factor receptor (EGFR) gene, small deletions in exon 19 and a point mutation in exon 21 (L858R) may be considered medically necessary to predict an improved response to afatinib (Gilotrif ), erlotinib (Tarceva ), or gefitinib (Iressa ) in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded. Analysis of EGFR mutations that are positive for the T790M gene may be considered necessary to predict an improved response to osimertinib (Tagrisso ) as a first-line treatment or after progression with platinum chemotherapy, afatinib, erlotinib, or gefitinib. Analysis of mutations within the EGFR gene may be medically necessary to predict an improved response to necitumumab (Portrazza ) in patients with advanced squamous cell lung cancer, in combination with platinum chemotherapy. Analysis of somatic rearrangement mutations of the anaplastic lymphoma kinase (ALK) gene may be considered medically necessary to predict treatment response to alectinib (Alcensa ), brigatinib (Alunbrig ), ceritinib (Zykadia ), and crizotinib (Xalkon ) in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded. Analysis of mutations within the ROS1 gene may be considered medically necessary to predict treatment response to crizotinib (Xalkon ) in patients with advanced lung adenocardinoma (Lindeman, 2013; Leighl, 2014); Kerr, 2014; NICE, 2013). Limitations: Other molecular analyses related to targeted therapy for lung cancer are considered investigational/experimental and therefore not medically necessary, including: 1. Small deletions in exon 19 and a point mutation in exon 21 (L858R), which are types of somatic mutations within the EGFR gene, for patients with advanced squamous cell NSCLC. EGFR testing would be considered for advanced squamous cell NSCLC if mutation-directed therapy is being considered. 2. Other EGFR mutations within exons or other applications related to NSCLC. 3. Other somatic rearrangement mutations of the ALK gene. 2

3 4. Somatic mutations of the Kirsten rat sarcoma (KRAS) gene to predict the efficacy of anti-egfr monoclonal antibody cetuximab in NSCLC. 5. Genetic alterations in the genes ROT, MET, BRAF, and HER2 for targeted therapy in patients with NSCLC. All other uses of genetic testing for lung cancer are considered investigational/experimental and, therefore, medically unnecessary. Alternative covered services: None. Background Lung cancer is one of the most commonly diagnosed cancers. In 2016, an estimated 224,390 Americans were diagnosed with the disease. Lung cancer has historically had high mortality rates; an estimated 158,080 Americans died from the disease, the most of any cancer type. The five-year survival rate from the disease has remained low, rising only from 12.2 percent to 18.7 percent between and (Howlader, 2016). Part of the difficulty in treating lung cancer is that 57 percent of new cases are metastasized ( distant ) to other parts of the body at the time of diagnosis. For these patients, chemotherapy has traditionally been the only recommended treatment option, and the five-year survival rate for these patients is just 4.3 percent, according to the National Cancer Institute (Howlader, 2016). Improved treatments for advanced lung cancer are needed. Recent developments have identified several drugs (afatinib, erlotinib, and gefitinib) that can target therapy to persons with somatic mutations in EGFR genes (which traditional chemotherapy does not do) for advanced NSCLC, in particular adenocardinoma (which accounts for 40 percent of all lung cancers). These drugs are much better tolerated by lung cancer patients compared to platinum chemotherapy and have been approved by the U.S. Food and Drug Administration (FDA) as first- and second-line treatments. Classifying molecular arrangements helps predict which patients with advanced lung adenocarcinoma will likely have extended progression-free survival (PFS) and fewer side effects to these targeted therapies than traditional chemotherapy, but not overall survival (OS) to date. In particular, small deletions in exon 19 and a point mutation in exon 21 (L858R) predict an improved response to afatinib or erlotinib. These therapies were developed after discovering the EGFR mutation exists in about 15 percent of lung cancer patients. Gefitinib was one of two first-generation treatments approved by the FDA in 2003 as a second-line treatment for NSCLC (after platinum chemotherapy); it was taken off the market by the 3

4 manufacturer two years later, and returned as a first-line therapy as approved by the FDA in Erlotinib was the other first-generation treatment, approved by the FDA in Afatinib is a secondgeneration treatment for persons with EGFR mutations, approved in Osimertinib is a third-generation therapy that was FDA approved in November This therapy was developed as first- and second-generation targeted therapies stopped working after cancer mutates; two-thirds of these patients tested positive for the T790M mutation, to which osimertinib is sensitive. Targeted therapy for those patients with somatic rearrangements of the ALK gene will likely have improved outcomes when treated with alectinib, ceritinib, or crizotinib. These drugs were approved by the FDA in December 2015, April 2014, and November 2013, respectively. The ALK gene exists in about 5 percent of NSCLC patients. One of these drugs (crizotinib) was also approved by the FDA in March 2016 for NSCLC patients with the ROS1 mutation, which has been observed in 1 percent of NSCLC patients. Squamous cell lung cancer accounts for the minority of the NSCLC population. Only one targeted therapy drug (necitumumab), approved by the FDA in November 2015, is available for persons with the EGFR mutation. Currently, there are no targeted therapies for small cell lung cancer approved by the FDA, as trials to g identify such treatments continue. The KRAS mutation is the most common mutation in NSCLC, occurring in 25 percent of cases. However, despite numerous trials using animals, no effective targeted therapy for this mutation has yet been identified (Lindeman, 2013; Leighl, 2014; Kerr, 2014; NICE, 2013; NCCN, 2018). Testing has become more common in advanced lung cancer cases. In a study of 1787 cases referred to 38 medical centers in Italy, 78 percent underwent a test of at least one mutation, with EGFR (76 percent) and ALK (53 percent) easily being the most common mutations tested. Most found to have an EGFR mutation (90 percent) or an ALK mutation (74 percent) received targeted therapy (Gobbini, 2017). Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on December 1, Search terms were lung cancer, metastatic, 4

5 molecular testing, ROS1, ALK, and EFGR. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings The poor survival rates for patients with lung cancer (especially those with metastases), difficulties tolerating chemotherapy regimens, and improved knowledge of genetic abnormalities in lung cancer patients has led to development and approval of a series of drugs that target cancerous cells. The 2013 guideline from the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology (AMP) recommends specific procedures for testing NSCLC patients for EGFR and ALK status (Lindeman, 2013). This guideline was soon endorsed by the American Society of Clinical Oncology (Leighl, 2014), the European Society for Medical Oncology (Kerr, 2014), and the UK s National Institute for Health Care and Excellence (NICE, 2013). The 2017 National Comprehensive Cancer Network guidelines recommends screening as standard treatment for EGFR and ALK, but also testing for ROS1, RET, BRAF, HER2 and MET alterations (NCCN, 2018, cited in Lau, 2017). The three-group guideline suggests that patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. Furthermore, the groups recommend lung cancer patients with squamous cell carcinomas, small cell carcinoma, or large cell carcinoma lacking any immunohistochemistry evidence of adenocarcinoma should not be tested for EGFR and ALK mutations. The groups also indicated that testing should be conducted for Stage IV patients at time of diagnosis, and for those suitable for therapy at time for progression who were not previously tested. The guideline leaves the decision to test NSCLC patients with Stage I, II, or III disease to the individual oncology team, in conjunction with laboratory managers. Fresh, frozen, or alcohol-fixed specimens for polymerase chain reaction-based EGFR mutations should be used. Laboratories, including a pathologist, should use an ALK fluorescence in situ hybridization assay with dual-labeled break-apart probes for ALK mutation testing. The standard for mutation testing in advanced lung cancer is tissue samples from biopsy, which takes two weeks for results to be known (Adamson, 2013). However, immunohistochemistry, a low-cost and 5

6 rapid technique from blood samples, can be used instead. Studies show that this approach is accurate for ALK and ROS1 mutations; however, mutant-specific antibodies against EGFR demonstrate a good specificity but a low-to-fair sensitivity, and caution should be taken in detecting this mutation (Rossi, 2016). Other meta-analyses agree that immunohistochemistry provides accurate results for EGFR testing (Chen, 2014; Dahabreh, 2010). A 2017 review reports that using circulating free tumor-derived DNA in blood plasma does not detect as many mutations as does tissue biopsy, but represents a promising, alternative diagnostic approach to molecular testing (Normanno, 2017). Inadequate amounts of tissue samples are not uncommon in testing for lung cancer mutations, and thus circulating tumor DNA from plasma represents a viable alternative means of testing (Sholl, 2017). Hybrid capture next-generation sequencing is being used more often when testing fails to identify a genetic mutation. In one study of 100 advanced lung cancer patients with negative or inconclusive results after testing, mutations identified by next-generation sequencing changed the treatment in 42.6 percent of the patients (Rozenblum, 2017). The Lux-trial program of the Boehringer Ingelheim pharmaceutical company (Ingelheim am Rhein, Germany) comprises more than 10 trials worldwide, including lung (LUX-Lung) and other cancers. Begun in the mid-2000s, the program incorporates a LUX-Lung component, focusing on targeted therapies for lung cancer. The initial results of LUX-Lung 1 were released in December 2010, and subsequent results followed in 2014, 2015, and The FDA action to approve erlotinib as targeted therapy for EGFR mutations for advanced NSCLC was based on clinical trials, principally a study of erlotinib versus platinum-based doublet chemotherapy (n = 174). Results showed consistently greater outcomes for the erlotinib group. Median progression-free survival was 10.4 months versus 5.2 months; median overall survival was 22.9 months vs months, which was not significant; and the objective response rate was 65 percent for the erlotinib arm versus 16 percent for the chemotherapy arm (Khozin, 2014). The FDA s 2013 decision to add afatinib to the list of targeted therapies for NSCLC relied on a LUX-Lung 3 Phase III Study with 345 patients that showed afatinib patients lived about as long as those on chemotherapy, with fewer side effects. Afatinib had a higher progression-free survival than pemetrexed and cisplatin chemotherapy (11.1 months versus 6.9 months). Those patients with EGFR mutations had an even higher median progression-free survival, of 13.6 months (Sequist, 2013). FDA approval of the only third-generation targeted therapy for EGFR mutations (osimertinib) resulted from positive outcomes in trials, specifically higher objective response rate, lower toxicity rates, and higher progression-free survival no increase in overall survival has yet been observed (Janne, 2015; Yang, 2016). FDA approval of crizotinib to be used as a first-line treatment for NSCLC patients whose malignancies are 6

7 ALK-positive was based largely on a clinical trial of 343 patients receiving oral crizotinib versus IV chemotherapy (pemetrexed plus cisplatin or carboplatin). The crizotinib group had a greater objective response rate than the chemotherapy group (74 versus 45 percent), and a longer median PFS (10.9 versus seven months). However, the one-year survival rate was 16 percent for the crizotinib group, which was actually less than the 21 percent survival rate for chemotherapy patients (Solomon, 2014). Similar results were the basis for the subsequent ALK mutations approved by the FDA (alectinib and certinib). As targeted therapy is now being used both in further clinical trials and in practice, a series of metaanalyses and systematic reviews have been produced, covering dozens of trials. Those reviewing the accuracy of metastatic tests show a strong ability to predict which patients qualify for targeted therapy (Chen, 2014; Qiu, 2015). Other meta-analyses focused on efficacy show targeted therapy that results from molecular analysis in advanced-stage NSCLC patients resulted in longer progression-free survival, greater objective response rate, and fewer adverse effects (Hotta, 2015; Lee, 2013; Liang, 2014). However, overall survival rates have yet to show any superior results from traditional chemotherapy, and survival within five years remains rare. The challenge of refining molecular analysis of genetic material of advanced NSCLC patients to improve efficacy of targeted therapy remains a high priority for future research. Studies have also addressed which biomarkers can predict effectiveness of targeted therapy against EGFR mutations. One meta-analysis of 61 studies found that the KRAS mutation is superior to the phosphatase and tensin homolog deficiency and PIK3CA mutation for objective response rate, overall survival, and progression free survival (Wang, 2015). Policy updates: A total of two guideline/other references and four peer-reviewed references have been added to, and two guideline/other references removed from this policy in December, A total of four professional guidelines/other references and five peer-reviewed references have been added to this policy in January Summary of clinical evidence: Citation Wang (2015) Predictors of outcomes after EGFR-specific targeted therapy for several biomarkers Content, Methods, Recommendations Meta-analysis of 61 studies, three predictors of anti-egfr agents in lung cancer (KRAS mutation, PTEN deficiency, PIK3CA mutation). ORR, OS, and PFS compared. KRAS superior for OSS (0.42), compared to PTEN and PIK3CA (0.82, 1.08). KRAS superior for OS (1.37), compared to PTEN and PIK3CA (0.88, 0.79). KRAS also an effective prognostic marker for PFS (1.33) 7

8 Citation Hotta (2015) Survival benefits in patients with targeted therapy for NSCLC Qiu (2015) Are circulating tumor DNA effective for the detection of EGFR mutation in NSCLC Chen (2014) Are immunohistochemical methods adequate to detect EGFR mutations Liang (2014) Do TKI inhibitors improve outcomes for patients with certain mutations Lee (2013) Does EGFR inhibitor raise progression free-survival and overall survival (PFS and OS) Dahabreh (2010) Content, Methods, Recommendations 18 Phase III trials investigating EGFR and ALK mutations. PFS greater, no difference in OS. 27 trials, 3110 participants. Circulating tumor DNA is a highly specific and effective way to detect EGFR mutations. 15 trials; looked at efficacy of anti E746-E750 antibody. Immunohistochemistry alone is sufficient for detecting EGFR mutations. Molecular-based analyses needed if anti E746-E750 results are negative. 20 Phase II and III controlled trials, 10,834 participants. Increases in PFS and ORR for patients qualifying for targeted therapy. No increase in OS and disease control rates. 23 trials, 14,570 participants. EGFR/tyrosine-kinase inhibitor (TKI) therapy extends PFS, but not OS. Are certain EGFR mutations predictors of responses to TKI targeted therapy 59 trials, 3,101 participants eligible for EGFR mutation. EGFR mutations accurately predicted response to single-agent TKI therapy. References Professional society guidelines/other: Hayes Inc. Genetic Test Evaluation Report. Anaplastic Lymphoma Kinase (ALK) Gene Rearrangement Testing in Non-Small Cell Lung Cancer (NSCLC). Lansdale PA: Hayes, Inc., July Hayes Inc. Genetic Test Evaluation Report. ERCC1 Expression Analysis in Non-Small Cell Lung Cancer (NSCLC). Lansdale PA: Hayes, Inc., January 17, Hayes Inc. Genetic Testing Evaluation Report. VeriStrat to Predict Response to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Non-Small Cell lung Cancer (NSCLC). Lansdale PA: Hayes, Inc., updated April Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, , National Cancer Institute. Bethesda MD. Accessed December 1,

9 Kerr KM, Bubendorf L, Edelman MJ, et al. ESMO consensus guidelines: pathology and molecular biomarkers for non-smal-cell lung cancer. Ann Oncol. 2014;25(9): Lau KW, Seng C, Lim TKH, Tan DSW. Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer. Ann Transl Med. 2017;5(18):372. Leighl NB,m Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cancer/association for Molecular Pathology guideline. J Clin Oncol. 2014;32(32): Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer [trunc]. Arch Pathol Lab Med. 2013;137(6): Meleth S, Reeder-Hayes K, Ashok M, et al. Technology Assessment of Molecular Pathology Testing for the Estimation of Prognosis for Common Cancers. AHRQ Technology Assessment Program, May 29, Accessed December 1, National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Updated Version 6, National Comprehensive Cancer Network (NCCN). NCCN Guideline with NCCN Evidence Blocks. Non- Small Cell Lung Cancer. Version 1, National Institute for Health Care and Excellence (NICE). EGFR-TK mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer. London (UK): National Institute for Health Care and Excellence. August 2013, 46 pp. Accessed December 1, Peer-reviewed references: Adamson RT. Biomarkers and molecular profiling in non-small cell lung cancer: an expanding role and its managed care implications. Am J Manag Care. 2013;19(19 Suppl):s Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: A double blind, randomized, phase III study of maintenance eerlotinib versus placebo following nonprogression with first-line platinum-based 9

10 chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27:(15_suppl):8001. Chen Z, Liu HB, Yu CH, Wang Y, Wang L, Song Y. Diagnostic value of mutation-specific antibodies for immunohistochemical detection of epidermal growth factor receptor mutations in non-small cell lung cancer: a meta-analysis. PloS One. 2014;9(9):e Dahabreh IJ, LInardou H, Siannis F, Kosmidis P, Bafaloukos D, Murray S. Somatic EGFR mutations and gene copy gain as predictive biomarkers for response to tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res. 2010;16(1): debiase D, Visani M, Malapelle U, et al. Next-generation sequencing of lung cancer EGFR exons allows effective molecular diagnosis of small routine samples (cytology and biopsy). PLoS One. 2013;23(8): doi /journal.pone Gautschi O, Dingmans AM, Crowe S, et al. VeriStrat has a prognostic value for patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab in the first line: pooled analysis of SAKK19/05 and NTR528. Lung Cancer. 2013;79(1): Gobbini E, Galetta D, Tiseo M, et al. Molecular profiling in Italian patients with advanced non-small-cell lung cancer: An observational prospective study. Lung Cancer. 2017;111: Hotta K, Kato Y, Leighl N, et al. Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. PLoS One. 2015;10(3); doi: /journal.pone Khozin S, Blumenthal GM, Jiang X, et al. U.S. Food and Drug Administration approval summary: Erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. Oncologist. 2014;19(7): Janne PA, Yang JC-H, Kim D-W, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372: Kuiper JL, Lind JS, Groen HJ, et al. VeriStrat has prognostic value in advanced stage NSCLC patients treated with erlotinib and sorafenib. Br J Cancer. 2012;107(11): Lee CK, Brown C, Gralla RJ, et al. Impact of EGFR inhibitor in non-small cell lung cancer on progressionfree and overall survival: a meta-analysis. J Natl Cancer Inst. 2013;105: Liang W, Wu X, Hong S, et al. Multi-targeted antiangiogenic tyrosine kinase inhibitors in advanced nonsmall cell lung cancer: meta-analyses of 20 randomized controlled trials and subgroup analyses. PLoS One. 2014;9(10): doi /journal.pone

11 Lin L, Asthana S, Chen E, et al. Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer. Proc Natl Acad Sci USA. 2014;111(7):E Mazzoni F, Rotella V, Pratesi N, et al. From clinical trials to clinical practice: predictors of response to erlotinib in advanced non-small cell lung cancer patients pretreated with chemotherapy. Tumori. 2011;97(2): Normanno N, Denis MG, Thress KS, Ratcliffe M, Reck, M. Guide to detecting epidermal growth factor receptor (EGFR) mutations in ctdna of patients with advanced non-small-cell lung cancer. Oncotarget. 2017;8(7): Pecuchet N, Bigot F, Henni M, Fabre E. Therapeutic impact of molecular diagnosis in metastatic nonsmall cell lung cancer: targeted therapies in Rev Pneumol Clin. 2014;70(1-2): Qiu M, Wang J, Xu Y, et al. Circulating tumor DNA is effective for the detection of EGFR mutation in nonsmall cell lung cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2015;24(1): Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361: Rossi G, Ragazzi M, Tamagini I, et al. Does immunohistochemistry represent a robust alternative technique in determining drugable predictive gene alterations in non-small cell lung cancer? Curr Drug Targets. 2016;18(1): Rozenblum AB, Ilouze M, Dudnik E, et al. Clinical Impact of Hybrid Capture-Based Next-Generation Sequencing on Changes in Treatment Decisions in Lung Cancer. J Thorac Oncol. 2017;12(2): Sequist LV, Yang JC-H, Yamamoto M, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31: Sholl L. Molecular diagnostics of lung cancer in the clinic. Transl Lung Cancer Res. 2017;6(5): Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23): Vignot S, Frampton GM, Soria JC, et al. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small cell lung cancer. J Clin Oncol. 2013;31(17): Wang Y, Qu X, Shen HC, Wang K, Liu Q, Du JJ. Predictive and prognostic biomarkers for patients treated with anti-egfr agents in lung cancer: a systemic review and meta-analysis. Asian Pac J Cancer Prev. 2015;16(11):

12 Yang J, Ramalingam SS, Janne PA, Cantarini M, Mitrsudomi T. LBA2 PR: osimertinib (AZD9291) in pretreated patients with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J Thorac Oncol. 2016;11(4 Suppl):S CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comments EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer), gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L8610Q) Unlisted molecular pathology procedure (ALK) ICD-10 Code Description Comments C34.0X Malignant neoplasm of main bronchus 5 th digit 0,1,2 C34.1X Malignant neoplasm of upper lobe, bronchus or lung 5 th digit 0,1,2 C34.2 Malignant neoplasm of middle lobe, bronchus or lung C34.3X Malignant neoplasm of lower lobe, bronchus or lung 5 th digit 0,1,2 C34.8X Malignant neoplasm of overlapping lobe, bronchus or lung 5 th digit 0,1,2 C34.9X Malignant neoplasm of unspecified site, bronchus or lung 5 th digit 0,1,2 HCPCS Level II Code N/A Description Comments 12