Liquid Biopsy Working Group Disclosures and Privacy Policy

Purpose of the Working Group: A multidisciplinary group was convened with the goal of creating a practical guideline for the routine use of liquid biopsy in aNSCLC among community oncologists. Specifically, the objectives of the meeting were to discuss the unmet needs related to genomic testing in aNSCLC, and to review the evidence supporting the use of liquid biopsy before first-line therapy and at disease progression. (See References below for data reviewed by the LBWG) The purpose of this review is to disseminate a consensus from the working group on practical guidance and recommendations to help community oncologists make informed decisions regarding the use of liquid biopsy in routine practice.

Funding/Support: The working group received funding support from Guardant Health, Inc., including meeting support, fees, the website platform and website hosting and maintenance.

Role of the Funder/Sponsor: Guardant Health had no role in the design and conduct of the recommendations; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The researchers worked independently without input from Guardant Health.

Privacy Policy for Liquid Biopsy for Lung Cancer Website (the “Website”)

NOTE: The clinical information provided on the Website is targeted for US clinicians. If you are located outside of the US, please understand that the Website was not designed for international privacy compliance.

When you use the Website, the following actions will take place:1. Cookies. We will use cookies to track visitors to the Website. We will use the information to send you further educational or promotional information. We will also be able to track when you visit the Website again. We track visits to the Website using visitor logs and tracking codes to compile anonymous aggregate statistics. This aggregate information includes anonymous website, application and device statistics.2. Voluntary Information and Use of Personal Data. When you click on “View Algorithm” or “View Recommendations” or send us an email, you consent to our secure storage of thepersonal information which you provide to us and to our use of it to send you the requested documents, the presentation, respond to your inquiries or to provide you with other educational and promotional materials.3. Protection of Information. Guardant Health will take reasonable and appropriate precautions to protect personal information in its possession from loss, misuse, and unauthorized access, disclosure, alteration and destruction. It is important to remember, however, that no system can provide 100% security at all times. Accordingly, we cannot guarantee the privacy and security of information stored on our systems.

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Publication References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30.

2. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-550.

3. National Cancer Institute. SEER Cancer Statistics Review, 1975-2015. Available at https://seer.cancer.gov/csr/1975_2015/results_merged/sect_15_lung_bronchus.pdf. Accessed July 24, 2018.

4. Kris MG, Johnson BE, Berry LD et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998-2006.

5. NCCN Guidelines Version 1.2019 Non-small Cell Lung Cancer. 2018. Available at https://www.Nccn.Org/professionals/physician_gls/f_guidelines.Asp. Accessed October 29, 2018.

6. Lindeman NI, Cagle PT, Aisner DL et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn 2018;20:129-159.

7. Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-2388.

8. Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-128.

9. Mok TS, Wu YL, Ahn MJ et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629-640.

10. Rosell R, Carcereny E, Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-246.

11. Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-3334.

12. Soria JC, Ohe Y, Vansteenkiste J et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113-125.

13. Wu YL, Zhou C, Hu CP et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213-222.

14. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-742.

15. Kim ST, Banks KC, Lee S et al. Prospective feasibility study for using cell-free circulating tumor DNA-guided therapy in refractory metastatic solid cancers: an interim analysis. JCO Precis Oncol 2017;1:1-15.

16. Larkins E, Blumenthal GM, Chen H et al. FDA approval: Alectinib for the treatment of metastatic, ALK-positive non-small cell lung cancer following crizotinib. Clin Cancer Res 2016;22:5171-5176.

17. Peters S, Camidge DR, Shaw AT et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017;377:829-838.

18. Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-2394.

19. Shaw AT, Ou SH, Bang YJ et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014;371:1963-1971.

20. Soria JC, Tan DSW, Chiari R et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet 2017;389:917-929.

21. Planchard D, Smit EF, Groen HJM et al. Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: An open-label, phase 2 trial. Lancet Oncol 2017;18:1307-1316.

22. Drilon A, Rekhtman N, Arcila M et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol 2016;17:1653-1660.

23. Gautschi O, Milia J, Filleron T et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol 2017;35:1403-1410.

24. Yoh K, Seto T, Satouchi M et al. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): An open-label, multicentre phase 2 trial. Lancet Respir Med 2017;5:42-50.

25. Drilon AE, Camidge DR, Ou SI et al. Efficacy and safety of crizotinib in patients with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol 2016:34(suppl 15; abstr 108).

26. Camidge DR, Ou SI, Shapiro G et al: Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 2014:34(suppl 15; abstr 8001).

27. Mazieres J, Barlesi F, Filleron T et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol 2016;27:281-286.

28. Carbone DP, Reck M, Paz-Ares L et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376:2415-2426.

29. Hellmann MD, Ciuleanu TE, Pluzanski A et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018;378:2093-2104.

30. Thompson JC, Yee SS, Troxel AB et al. Detection of therapeutically targetable driver and resistance mutations in lung cancer patients by next-generation sequencing of cell-free circulating tumor DNA. Clin Cancer Res 2016;22:5772-5782.

31. Villaflor V, Won B, Nagy R et al. Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer. Oncotarget 2016;7:66880-66891.

32. Hagemann IS, Devarakonda S, Lockwood CM et al. Clinical next-generation sequencing in patients with non-small cell lung cancer. Cancer 2015;121:631-639.

33. Gutierrez ME, Choi K, Lanman RB et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer 2017;18:651-659.

34. Abernethy AP, Arunachalam A, Burke T et al. Real-world first-line treatment and overall survival in non-small cell lung cancer without known EGFR mutations or ALK rearrangements in US community oncology setting. PLoS One 2017;12:e0178420.

35. Hussein M, Richards DA, Ulrich B et al. Biopsies in initial diagnosis of non-small cell lung cancer in US community oncology practices: implications for first-line immunotherapy: Topic: Medical oncology. J Thorac Oncol 2016;11:S249-S250(abstr ORAL01.02).

36. Henk HJ, Ray S. Treatment patterns and healthcare costs among patients with advanced non-small-cell lung cancer. Lung Cancer Manage 2013;2:189-197.

37. Diaz LA, Jr., Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014;32:579-586.

38. Bettegowda C, Sausen M, Leary RJ et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014;6:224ra224.

39. Singh AP, Li S, Cheng H. Circulating DNA in EGFR-mutated lung cancer. Ann Transl Med 2017;5:379.

40. Burstein HJ, Krilov L, Aragon-Ching JB et al. Clinical Cancer Advances 2017: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 2017;35:1341-1367.

41. Oxnard GR, Thress KS, Alden RS et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016;34:3375-3382.

42. Merker JD, Oxnard GR, Compton C et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol 2018;36:1631-1641.

43. Hu Y, Ulrich B, Supplee J et al. False positive plasma genotyping due to clonal hematopoiesis. Clin Cancer Res 2018;24:4437-4443.

44. Lanman RB, Mortimer SA, Zill OA et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One 2015;10:e0140712.

45. Lebofsky R, Decraene C, Bernard V et al. Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Mol Oncol 2015;9:783-790.

46. Janku F, Zhang S, Waters J et al. Development and validation of an ultradeep next-generation sequencing assay for testing of plasma cell-free DNA from patients with advanced cancer. Clin Cancer Res 2017;23:5648-5656.

47. Karachaliou N, Mayo-de las Casas C, Queralt C et al. Association of EGFR L858R mutation in circulating free DNA with survival in the EURTAC trial. JAMA Oncol 2015;1:149-157.

48. Sacher AG, Paweletz C, Dahlberg SE et al. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Oncol 2016;2:1014-1022.

49. Schwaederle M, Husain H, Fanta PT et al. Use of liquid biopsies in clinical oncology: Pilot experience in 168 patients. Clin Cancer Res 2016;22:5497-5505.

50. 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;12:258-268.

51. Mccoach CE, Blakely CM, Banks KC et al. Clinical utility of cell-free DNA for the detection of ALK fusions and genomic mechanisms of ALK inhibitor resistance in non-small cell lung cancer. Clin Cancer Res 2018;24:2758-2770.

52. Nakamura Y, Yoshino T. Clinical utility of analyzing circulating tumor DNA in patients with metastatic colorectal cancer. The Oncologist 2018;23:1-8.

53. Sacher AG, Komatsubara KM, Oxnard GR. Application of plasma genotyping technologies in non-small cell lung cancer: A practical review. J Thorac Oncol 2017;12:1344-1356.

54. Rolfo C, Mack PC, Scagliotti GV et al. Liquid biopsy for advanced non-small cell lung cancer (NSCLC): A statement paper from the IASLC. J Thorac Oncol 2018;13:1248-1268.

55. Odogwu L, Mathieu L, Goldberg KB et al. FDA benefit-risk assessment of osimertinib for the treatment of metastatic non-small cell lung cancer harboring epidermal growth factor receptor T790M mutation. The Oncologist 2018;23:353-359.

56. Redig AJ, Costa DB, Taibi M et al. Prospective study of repeated biopsy feasibility and acquired resistance at disease progression in patients with advanced EGFR mutant lung cancer treated with erlotinib in a phase 2 trial. JAMA Oncol 2016;2:1240-1242.

57. Lokhandwala T, Bittoni MA, Dann RA et al. Costs of diagnostic assessment for lung cancer: a Medicare claims analysis. Clin Lung Cancer 2017;18:e27-e34.

59. PlasmaSELECTTM-R 64. Available at http://www.Personalgenome.Com/pharma-biotech-companies/liquid-biopsy/. Accessed May 31, 2018.

60. Guardant360. Available at http://www.Guardanthealth.Com/guardant360/. Accessed May 31, 2018.

61. FoundationACT®. Available at https://www.Foundationmedicine.Com/genomic-testing/foundation-act. Accessed May 31, 2018.

62. Liquid GPS. Available at http://nanthealth.Orbitdesignworks.Com/liquid-gps/. Accessed May 31, 2018.

63. InVisionFirstTM-Lung. Available at https://www.Inivata.Com/our-products/invisionfirst/. Accessed May 31, 2018.

64. CancerInterceptTM-Monitor-frequently-asked-questions. Available at https://www.Pathway.Com/cancerintercept-monitor-frequently-asked-questions/. Accessed May 31, 2018.

65. Target SelectorTM Biomarker. Available at https://biocept.Com/biomarkers-test/. Accessed May 31, 2018.

66. Genestrat® Genomic Test. Available at https://www.Biodesix.Com/genestrat/. Accessed May 31, 2018.

67. Cobas® EGFR Mutation Test v2. Available at https://molecular.Roche.Com/assays/cobas-egfr-mutation-test-v2/. Accessed May 31, 2018.

68. Khodakov D, Wang C, Zhang DY. Diagnostics based on nucleic acid sequence variant profiling: PCR, hybridization, and NGS approaches. Adv Drug Deliv Rev 2016;105:3-19.

69. Engstrom PF, Bloom MG, Demetri GD et al. NCCN molecular testing white paper: effectiveness, efficiency, and reimbursement. J Natl Compr Canc Netw 2011;9 Suppl 6:S1-16.

70. Kurzrock R, Colevas AD, Olszanski A et al. NCCN oncology research program’s investigator steering committee and NCCN best practices committee molecular profiling surveys. J Natl Compr Canc Netw 2015;13:1337-1346.

71. Mellert H, Foreman T, Jackson L et al. Development and clinical utility of a blood-based test service for the rapid identification of actionable mutations in non-small cell lung carcinoma. J Mol Diagn 2017;19:404-416.

72. Kuderer NM, Burton KA, Blau S et al. Comparison of 2 commercially available next-generation sequencing platforms in oncology. JAMA Oncol 2017;3:996-998.

73. U.S. Food and Drug Administration. 2016 19 Dec. Cobas EGFR Mutation Test v2. Available at https://www.Fda.Gov/drugs/informationondrugs/approveddrugs/ucm504540.Htm. Accessed March 27, 2018.

74. Discussion paper on laboratory developed tests (LDTs). January 13, 2017. Available at https://www.Fda.Gov/downloads/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/laboratorydevelopedtests/ucm536965.Pdf. Accessed April 03, 2018.

75. Levy KD, Pratt VM, Skaar TC et al. FDA’s draft guidance on laboratory-developed tests increases clinical and economic risk to adoption of pharmacogenetic testing. J Clin Pharmacol2015;55:725-727.

76. Rosenman MB, Decker B, Levy KD et al. Lessons learned when introducing pharmacogenomic panel testing into clinical practice. Value Health 2017;20:54-59.

77. Draft guidance for industry, Food and Drug Administration staff, and clinical laboratories: Framework for regulatory oversight of laboratory developed tests (LDTs). Available at http://www.Fda.Gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm416685.Pdf. Accessed on April 03, 2018.

78. Tempero M. Molecular diagnostics: Another battle brewing. J Natl Compr Canc Netw2018;16:225.

79. Dienstmann R, Elez E, Argiles G et al. Analysis of mutant allele fractions in driver genes in colorectal cancer – biological and clinical insights. Mol Oncol 2017;11:1263-1272.

80. Phallen J, Sausen M, Adleff V et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med 2017;9:eaan2415.

81. Chen KZ, Lou F, Yang F et al. Circulating tumor DNA detection in early-stage non-small cell lung cancer patients by targeted sequencing. Sci Rep 2016;6:31985.

82. Szpechcinski A, Chorostowska-Wynimko J, Struniawski R et al. Cell-free DNA levels in plasma of patients with non-small-cell lung cancer and inflammatory lung disease. Br J Cancer 2015;113:476-483.

83. Vendrell JA, Mau-Them FT, Beganton B et al. Circulating cell free tumor DNA detection as a routine tool for lung cancer patient management. Int J Mol Sci 2017;18:264.

84. Singh AP. Circulating tumor DNA in non–small-cell lung cancer: a primer for the clinician. JCO Precis Oncol 2017:1-13.

85. Hu Y, Alden RS, Odegaard JI et al. Discrimination of germline EGFR T790M mutations in plasma cell-free DNA allows study of prevalence across 31,414 cancer patients. Clin Cancer Res 2017;23:7351-7359.

86. Yang M, Topaloglu U, Petty WJ et al. Circulating mutational portrait of cancer: Manifestation of aggressive clonal events in both early and late stages. J Hematol Oncol 2017;10:100.

87. Krug AK, Enderle D, Karlovich C et al. Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma. Ann Oncol 2018;29:700-706.

88. Dietz S, Schirmer U, Merce C et al. Low input whole-exome sequencing to determine the representation of the tumor exome in circulating DNA of non-small cell lung cancer patients. PLoS One 2016;11:e0161012.

89. Zhang YC, Zhou Q, Wu YL. The emerging roles of NGS-based liquid biopsy in non-small cell lung cancer. J Hematol Oncol 2017;10:167.

90. Davis AA, Chae YK, Agte S. Comparison of tumor mutational burden (TMB) across tumor tissue and circulating tumor DNA (ctDNA). J Clin Oncol 35;2017(suppl 15; abstr e23028).

91. Corcoran RB, Chabner BA. Application of cell-free DNA analysis to cancer treatment. N Engl J Med 2018;379:1754-1765.