NSCLC Treatment Paradigm
Expert View on the Evolving Treatment Paradigm in Advanced NSCLC

Released: June 23, 2020

Expiration: June 22, 2021

Matthew Gubens
Matthew Gubens, MD, MS

Activity

Progress
1
Course Completed

  1. Li T, Kung HJ, Mack PC, et al. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol. 2013;31:1039-1049.
  2. Tsao AS, Scagliotti GV, Bunn PA, et al. Scientific advances in lung cancer 2015. J Thorac Oncol. 2016;11:613-638.
  3. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551.
  4. Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33:3488-3515.
  5. 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, and Association for Molecular Pathology. J Thorac Oncol. 2013;8:823.
  6. Bernabé R, Hickson N, Wallace A, Blackhall FH. What do we need to make circulating tumour DNA (ctDNA) a routine diagnostic test in lung cancer? Eur J Cancer. 2017;81:66-73.
  7. Bauml J, Levy B. Clonal hematopoiesis: a new layer in the liquid biopsy story in lung cancer. Clin Cancer Res. 2018;24:4352-4354.
  8. Hirsh V. Turning EGFR mutation-positive non-small-cell lung cancer Into a chronic disease: optimal sequential therapy with EGFR tyrosine kinase inhibitors. Ther Adv Med Onc. 2018;10:1758834017753338.
  9. Ramalingam S, T Reungwetwattana, Chewaskulyong B, et al. Osimertinib vs standard of care (soc) egfr-tki as first-line therapy in patients (pts) with egfrm advanced NSCLC: FLAURA. Program and abstracts of the 2017 European Society for Medical Oncology Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA2_PR.
  10. 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.
  11. Osimertinib package insert. Wilmington, DE: AstraZeneca; 2019.
  12. Schiefer M, Hendriks L, Dinh T, et al. Current perspective: osimertinib-induced QT prolongation: new drugs with new side-effects need careful patient monitoring. Eur J Cancer. 2018;91:92-98.
  13. Piotrowska Z, Isozaki H, Lennerz JK, et al. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. 2018;8:1529-1539.
  14. Oxnard GR, Yang J C-H, Yu H, et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Ann Oncol. 2020;31:507-516.
  15. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167-2177.
  16. 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.
  17. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390:29-39.
  18. 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.
  19. Camidge DR, Kim HR, Ahn M-J, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379:2027-2039.
  20. Camidge DR, Peters S, Mok T, et al. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC. Program and abstracts of the 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, Illinois. Abstract 9043.
  21. Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018;29:2214-2222.
  22. Popat S, Kim HR, Ahn M, et al. Intracranial efficacy of brigatinib (brg) vs crizotinib (crz) in the phase 3 alta-1l trial. Program and abstracts of the 2018 European Society of Medical Oncology Congress. October 19-23, 2018; Munich, Germany. Abstract LBA58.
  23. Gainor FJ, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016;6:1118-1133.
  24. Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19:1654-1667.
  25. Shaw AT, Solomon BJ, Chiari R, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019;20:1691-1701.
  26. Solomon B, Shaw A, Ou S, et al. Phase 2 study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer. Program and abstracts of the 2017 Word Conference on Lung Cancer. October 15-18, 2017; Yokohama, Japan. Abstract OA 05.06.
  27. Lorlatinib package insert. New York, NY: Pfizer; 2018.
  28. Bauer TM, Felip E, Solomon BJ, et al. Clinical management of adverse events associated with lorlatinib. Oncologist. 2019;24:1103-1110.
  29. Crizotinib package insert. New York, NY: Pfizer; 2016.
  30. Entrectinib package insert. South San Francisco, CA: Genentech; 2019.
  31. Shaw AT, Solomon BJ, Chiari R, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019;20:1691-1701.
  32. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21:261-270.
  33. Doebele R, Ahn M, Siena S, et al. Efficacy and safety of entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Program and abstracts of the 2018 World Conference on Lung Cancer. September 23-26, 2018; Toronto, Canada. Abstract OA02.01.
  34. 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.
  35. Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:642-650.
  36. Drilon A. MET exon 14 alterations in lung cancer: exon skipping extends half-life. Clin Cancer Res. 2016;22:2832-2834.
  37. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26:47-51.
  38. Shaw AT, Riely GJ, Bang Y-J, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30:1121-1126.
  39. Wolf J, Seto T, Han J-Y, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study. ASCO 2019. Abstract 9004.
  40. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with METex14 skipping mutations. New Engl J Med. 2020;online ahead of print.
  41. 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;13:1403-1410.
  42. Cabozantinib package insert. Alameda, CA: Exelixis; 2019.
  43. Vandetanib package insert. Wilmington, DE. AstraZeneca; 2014.
  44. Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. Program and abstracts of the 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, Illinois. Abstract 102.
  45. Mendoza L. Clinical development of RET inhibitors in RET-rearranged non-small cell lung cancer: update. Oncol Rev. 2018;12:352.
  46. Subbiah V, Gainor JF, Rahal R, et al. Precision targeted therapy with BLU-667 for RET-Driven Cancers. Cancer Discov. 2018;8:836-849.
  47. Drilon AE, Oxnard G, Wirth L, et al. Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers. Program and abstracts of the 2019 World Conference on Lung Cancer; September 7 - 10, 2019; Barcelona, Spain. Abstract PL02.08.
  48. Gainor JF, Lee DH, Curigliano G, et al. Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC). Program and abstracts of the 2019 American Society of Clinical Oncology Annual Meeting; May 31 - June 4, 2019; Chicago, Illinois. Abstract 9008.
  49. Velcheti V, Bauer TM, Subbiah V, et al. LOXO-292, a potent, highly selective RET inhibitor, in MKI-resistant RET fusion-positive lung cancer patients with and without brain metastases. Program and abstracts of the 2017 World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan.
  50. McCormick F. K-Ras protein as a drug Target. J Mol Med (Berl). 2016;94:253-258.
  51. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543-550.
  52. Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575:217-223.
  53. Fakih M, O’Neil B, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. Program and abstracts of the 2019 American Society of Clinical Oncology Annual Meeting; May 31 - June 4, 2019; Chicago, Illinois. Abstract 3003.
  54. Janne P, et al. MRTX849 shows clinical activity in patients with KRAS G12C-mutant solid cancer. ESMO Open. 2016;1:e000023.
  55. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731-747.
  56. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378:731-739.
  57. Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. Program and abstracts of the 2017 American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, Illinois. Abstract LBA2501.
  58. Larotrectinib package insert.  Stamford, CT: Loxo Oncology; 2018
  59. Entrectinib package insert. Stamford, CT: Loxo Oncology; 2018.
  60. Planchard D. Multi kinases inhibitors with NTRK as a possible target. Program and abstracts of the 2019 European Society for Medical Oncology Congress; September 27 - October 1, 2019; Barcelona, Spain.
  61. Federman N, McDermott R. Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer. Expert Rev Clin Pharmacol. 2019;12:931-939.
  62. Hyman D, van Tilburg CM, Albert CM, et al. Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer. Program and abstracts of the 2019 European Society for Medical Oncology Congress; September 27 - October 1, 2019; Barcelona, Spain. Abstract 445PD.
  63. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Program and abstracts of the 2018 European Society for Medical Oncology Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17.
  64. Doebele R, Paz-Ares L, Farago AF, et al. Entrectinib in NTRK-fusion positive (NTRK-FP) non-small cell lung cancer (NSCLC): integrated analysis of patients enrolled in three trials (STARTRK-2, STARTRK-1 and ALKA-372-001). Program and abstracts of the 2019 American Association for Cancer Research; March 29 - April 3, 2019; Atlanta, Georgia. Abstract CT131.
  65. Lassan UN, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in trk fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach. Program and abstracts of the 2018 European Society for Medical Oncology Congress; October 19-23, 2018; Munich, Germany. Abstract 4090.
  66. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumours: pooled analysis of STARTRK-2, STARTRK-1, and ALKA-372-001. Program and abstracts of the 2018 European Society for Medical Oncology Asia Congress; November 23-25, 2018; Republic of Singapore, Asia.
  67. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in Metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078-2092.
  68. Reck M, Socinski MA, Cappuzzo F, et al. Primary pfs and safety analyses of a randomized phase iii study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMPOWER150). Program and abstracts of the 2017 European Society for Medical Oncology Immuno Oncology Congress; December 7-10, 2017; Geneva, Switzerland. Abstract LBA1_PR.
  69. Kowanetz M, Socinski MA, Zou W, et al. IMpower150: IMpower150: efficacy of atezolizumab plus bevacizumab and chemotherapy in 1L metastatic nonsquamous NSCLC across key subgroups. Program and abstracts of the 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT076.
  70. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288-2301.
  71. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:924-937.
  72. Atezolizumab package insert. South San Francisco, CA: Genentech; 2019.
  73. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-Small-cell lung cancer. N Engl J Med. 2018;379:2040-2051.
  74. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823-1833.
  75. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37:537-546.
  76. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393:1819-1830.
  77. Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. Program and abstracts of the 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, Illinois. Abstract LBA4
  78. Lee CK, Man J, Lord S, et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol. 2018;4:210-216.
  79. Lisberg A, Cummings A, Goldman JW, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J Thorac Oncol. 2018;13:1138-1145.
  80. Lisberg AE, Cummings AL, Goldman JW, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor (TKI) naïve patients with advanced NSCLC. Program and abstracts of the 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, Illinois. Abstract 9014.
  81. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30:839-844.
  82. Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N Engl J Med. 2017;377:2500-2501.
  83. Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus ipilimumab in lung Cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093-2104.
  84. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. Program and abstracts of the 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT077.
  85. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381:2020-2031.
  86. Borghaei H, Hellmann MD, Paz-Ares LG, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: results from CheckMate 227. Program and abstracts of the 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, Illinois. Abstract 9001.
  87. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Brit J Cancer. 2018;118:9-16.
  88. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714-1768.
  89. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158-168.
  90. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95.
  91. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148.
  92. Remon J, Mezquita A, Corral J, et al. Immune-related adverse events with immune checkpoint inhibitors in thoracic malignancies: focusing on non-small cell lung cancer patients. J Thorac Dis. 2018;10(Suppl 13):S1516-S1533.
  93. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377:1919-1929.
  94. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342-2350.
  95. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab versus placebo after chemoradiotherapy in stage III NSCLC: updated results from PACIFIC. Program and abstracts of the 2018 World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.01.
  96. Gray JE, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. Program and abstracts of the 2019 American Society of Clinical Oncology Annual Meeting; May 31 - June 4, 2019; Chicago, Illinois. Abstract 8526.
  97. Hui R, Ozguroglu M, Vilegas A, et al. Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study. Lancet Oncol. 2019;20:1670-1680.
  98. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-742.