1932

Abstract

The rapid evolution of treatment for advanced lung cancer is a story of how scientists have struggled to move from nonselective cytotoxic chemotherapy to personalized precision medicine. In this century, extraordinary advances have been made in the management of advanced and metastatic non–small cell lung cancer, especially in the development of small molecules targeting specific tyrosine kinase receptors and immune checkpoint inhibitors. These developments have led to a significant improvement in survival for lung cancer patients with metastatic disease. Now, the core guidelines to treat non–small cell lung cancer are based on the identification of targetable driver mutations and immune checkpoints. Continued investigations of newly identified druggable genetic alterations, explorations of biomarkers of immune checkpoint inhibitors, development of next-generation immunotherapy, and optimization of combination therapy are necessary to provide better treatment outcomes for lung cancer patients in the future.

[Erratum, Closure]

An erratum has been published for this article:
Erratum: Precision Management of Advanced Non–Small Cell Lung Cancer
Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-051718-013524
2020-01-27
2024-06-17
Loading full text...

Full text loading...

/deliver/fulltext/med/71/1/annurev-med-051718-013524.html?itemId=/content/journals/10.1146/annurev-med-051718-013524&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Bray F, Ferlay J, Soerjomataram I et al. 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68:394–424
    [Google Scholar]
  2. 2. 
    Molina JR, Yang P, Cassivi SD et al. 2008. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin. Proc. 83:584–94
    [Google Scholar]
  3. 3. 
    Sun S, Schiller JH, Gazdar AF 2007. Lung cancer in never smokers—a different disease. Nat. Rev. Cancer 7:778–90
    [Google Scholar]
  4. 4. 
    Sun Y, Ren Y, Fang Z et al. 2010. Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J. Clin. Oncol. 28:4616–20
    [Google Scholar]
  5. 5. 
    Rajeswaran A, Trojan A, Burnand B, Giannelli M 2008. Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer 59:1–11
    [Google Scholar]
  6. 6. 
    Ciuleanu T, Brodowicz T, Zielinski C et al. 2009. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374:1432–40
    [Google Scholar]
  7. 7. 
    Fossella FV, DeVore R, Kerr RN et al. 2000. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J. Clin. Oncol. 18:2354–62
    [Google Scholar]
  8. 8. 
    Scagliotti GV, Parikh P, von Pawel J et al. 2008. 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. 26:3543–51
    [Google Scholar]
  9. 9. 
    Sandler A, Gray R, Perry MC et al. 2006. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355:2542–50
    [Google Scholar]
  10. 10. 
    Reck M, von Pawel J, Zatloukal P et al. 2009. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J. Clin. Oncol. 27:1227–34
    [Google Scholar]
  11. 11. 
    Garon EB, Ciuleanu TE, Arrieta O et al. 2014. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384:665–73
    [Google Scholar]
  12. 12. 
    Reck M, Kaiser R, Mellemgaard A et al. 2014. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 15:143–55
    [Google Scholar]
  13. 13. 
    Thatcher N, Hirsch FR, Luft AV et al. 2015. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 16:763–74
    [Google Scholar]
  14. 14. 
    Pardoll DM. 2012. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12:252–64
    [Google Scholar]
  15. 15. 
    Cancer Genome Atlas Research Network 2012. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519–25
    [Google Scholar]
  16. 16. 
    Cancer Genome Atlas Research Network 2014. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543–50
    [Google Scholar]
  17. 17. 
    Liu L, Liu J, Shao D et al. 2017. Comprehensive genomic profiling of lung cancer using a validated panel to explore therapeutic targets in East Asian patients. Cancer Sci 108:2487–94
    [Google Scholar]
  18. 18. 
    Seto T, Matsumoto S, Yoh K et al. 2018. Contribution of nationwide genome screening in Japan (LC-SCRUM-Japan) to the development of precision medicine for non-small cell lung cancer. J. Clin. Oncol. 36:9085
    [Google Scholar]
  19. 19. 
    Jordan EJ, Kim HR, Arcila ME et al. 2017. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov 7:596–609
    [Google Scholar]
  20. 20. 
    Paik PK, Hasanovic A, Wang L et al. 2012. Multiplex testing for driver mutations in squamous cell carcinomas of the lung. J. Clin. Oncol. 30:7505
    [Google Scholar]
  21. 21. 
    Lynch TJ, Bell DW, Sordella R et al. 2004. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350:2129–39
    [Google Scholar]
  22. 22. 
    Lindeman NI, Cagle PT, Aisner DL et al. 2018. 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. Thorac. Oncol. 13:323–58
    [Google Scholar]
  23. 23. 
    Brewer MR, Yun CH, Lai D et al. 2013. Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. PNAS 110:E3595–604
    [Google Scholar]
  24. 24. 
    Kobayashi Y, Mitsudomi T. 2016. Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci 107:1179–86
    [Google Scholar]
  25. 25. 
    Pao W, Miller V, Zakowski M et al. 2004. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. PNAS 101:13306–11
    [Google Scholar]
  26. 26. 
    Fukuoka M, Wu YL, Thongprasert S et al. 2011. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J. Clin. Oncol. 29:2866–74
    [Google Scholar]
  27. 27. 
    Maemondo M, Inoue A, Kobayashi K et al. 2010. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362:2380–88
    [Google Scholar]
  28. 28. 
    Mitsudomi T, Morita S, Yatabe Y et al. 2010. 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 11:121–28
    [Google Scholar]
  29. 29. 
    Mok TS, Wu YL, Thongprasert S et al. 2009. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361:947–57
    [Google Scholar]
  30. 30. 
    Rosell R, Carcereny E, Gervais R et al. 2012. 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 13:239–46
    [Google Scholar]
  31. 31. 
    Zhou C, Wu YL, Chen G et al. 2011. 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 12:735–42
    [Google Scholar]
  32. 32. 
    Inoue A, Kobayashi K, Maemondo M et al. 2013. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann. Oncol. 24:54–59
    [Google Scholar]
  33. 33. 
    Zhou C, Wu YL, Chen G et al. 2015. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann. Oncol. 26:1877–83
    [Google Scholar]
  34. 34. 
    Spicer J, Calvert H, Vidal L et al. 2007. D7–02: Activity of BIBW2992, an oral irreversible dual EGFR/HER2 inhibitor, in non-small cell lung cancer (NSCLC) with mutated EGFR. J. Thorac. Oncol. 2:S410
    [Google Scholar]
  35. 35. 
    Sequist LV, Yang JC, Yamamoto N et al. 2013. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31:3327–34
    [Google Scholar]
  36. 36. 
    Wu YL, Zhou C, Hu CP et al. 2014. 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 15:213–22
    [Google Scholar]
  37. 37. 
    Yang JC, Wu YL, Schuler M et al. 2015. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 16:141–51
    [Google Scholar]
  38. 38. 
    Park K, Tan EH, O'Byrne K et al. 2016. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 17:577–89
    [Google Scholar]
  39. 39. 
    Wu YL, Cheng Y, Zhou X et al. 2017. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18:1454–66
    [Google Scholar]
  40. 40. 
    Giaccone G. 2005. EGFR point mutation confers resistance to gefitinib in a patient with non-small-cell lung cancer. Nat. Clin. Pract. Oncol. 2:296–97
    [Google Scholar]
  41. 41. 
    Takezawa K, Pirazzoli V, Arcila ME et al. 2012. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2:922–33
    [Google Scholar]
  42. 42. 
    Engelman JA, Zejnullahu K, Mitsudomi T et al. 2007. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–43
    [Google Scholar]
  43. 43. 
    Ludovini V, Bianconi F, Pistola L et al. 2011. Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J. Thorac. Oncol. 6:707–15
    [Google Scholar]
  44. 44. 
    Ho CC, Liao WY, Lin CA et al. 2017. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J. Thorac. Oncol. 12:567–72
    [Google Scholar]
  45. 45. 
    Nurwidya F, Takahashi F, Murakami A, Takahashi K 2012. Epithelial mesenchymal transition in drug resistance and metastasis of lung cancer. Cancer Res. Treat. 44:151–56
    [Google Scholar]
  46. 46. 
    Niederst MJ, Sequist LV, Poirier JT et al. 2015. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat. Commun. 6:6377
    [Google Scholar]
  47. 47. 
    Cross DA, Ashton SE, Ghiorghiu S et al. 2014. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4:1046–61
    [Google Scholar]
  48. 48. 
    Janne PA, Yang JC, Kim DW et al. 2015. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372:1689–99
    [Google Scholar]
  49. 49. 
    Mok TS, Wu YL, Ahn MJ et al. 2017. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376:629–40
    [Google Scholar]
  50. 50. 
    Ramalingam SS, Yang JC, Lee CK et al. 2018. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J. Clin. Oncol. 36:841–49
    [Google Scholar]
  51. 51. 
    Soria JC, Ohe Y, Vansteenkiste J et al. 2018. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378:113–25
    [Google Scholar]
  52. 52. 
    Ramalingam SS, Cheng Y, Zhou C et al. 2018. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Ann. Oncol. 29:Suppl. 8mdy424–063
    [Google Scholar]
  53. 53. 
    Saito H, Fukuhara T, Furuya N et al. 2019. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 20:625–35
    [Google Scholar]
  54. 54. 
    Blakely CM, Watkins TBK, Wu W et al. 2017. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49:1693–704
    [Google Scholar]
  55. 55. 
    Nakamura A, Inoue A, Morita S et al. 2018. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J. Clin. Oncol. 36:9005
    [Google Scholar]
  56. 56. 
    Chiu CH, Yang CT, Shih JY et al. 2015. Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768I mutations. J. Thorac. Oncol. 10:793–99
    [Google Scholar]
  57. 57. 
    Yang JC, Sequist LV, Geater SL et al. 2015. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 16:830–38
    [Google Scholar]
  58. 58. 
    Morris SW, Kirstein MN, Valentine MB et al. 1994. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263:1281–84
    [Google Scholar]
  59. 59. 
    Soda M, Choi YL, Enomoto M et al. 2007. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–66
    [Google Scholar]
  60. 60. 
    Shaw AT, Kim DW, Nakagawa K et al. 2013. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368:2385–94
    [Google Scholar]
  61. 61. 
    Solomon BJ, Mok T, Kim DW et al. 2014. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371:2167–77
    [Google Scholar]
  62. 62. 
    Shaw AT, Kim TM, Crino L et al. 2017. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 18:874–86
    [Google Scholar]
  63. 63. 
    Kim DW, Tiseo M, Ahn MJ et al. 2017. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J. Clin. Oncol. 35:2490–98
    [Google Scholar]
  64. 64. 
    Novello S, Mazieres J, Oh IJ et al. 2018. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann. Oncol. 29:1409–16
    [Google Scholar]
  65. 65. 
    Soria JC, Tan DSW, Chiari R et al. 2017. 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 389:917–29
    [Google Scholar]
  66. 66. 
    Peters S, Camidge DR, Shaw AT et al. 2017. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377:829–38
    [Google Scholar]
  67. 67. 
    Hida T, Nokihara H, Kondo M et al. 2017. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 390:29–39
    [Google Scholar]
  68. 68. 
    Gadgeel S, Peters S, Mok T et al. 2018. 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. 29:2214–22
    [Google Scholar]
  69. 69. 
    Toyokawa G, Seto T. 2015. Updated evidence on the mechanisms of resistance to ALK inhibitors and strategies to overcome such resistance: clinical and preclinical data. Oncol. Res. Treat. 38:291–98
    [Google Scholar]
  70. 70. 
    Lin JJ, Zhu VW, Yoda S et al. 2018. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J. Clin. Oncol. 36:1199–206
    [Google Scholar]
  71. 71. 
    Shaw AT, Felip E, Bauer TM et al. 2017. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 18:1590–99
    [Google Scholar]
  72. 72. 
    Lin JJ, Zhu VW, Schoenfeld AJ et al. 2018. Brigatinib in patients with alectinib-refractory ALK-positive NSCLC. J. Thorac. Oncol. 13:1530–38
    [Google Scholar]
  73. 73. 
    Bergethon K, Shaw AT, Ou SH et al. 2012. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin. Oncol. 30:863–70
    [Google Scholar]
  74. 74. 
    Neel DS, Allegakoen DV, Olivas V et al. 2019. Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. Cancer Res 79:546–56
    [Google Scholar]
  75. 75. 
    Shaw AT, Ou SH, Bang YJ et al. 2014. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 371:1963–71
    [Google Scholar]
  76. 76. 
    Awad MM, Katayama R, McTigue M et al. 2013. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N. Engl. J. Med. 368:2395–401
    [Google Scholar]
  77. 77. 
    Vaishnavi A, Schubert L, Rix U et al. 2017. EGFR mediates responses to small-molecule drugs targeting oncogenic fusion kinases. Cancer Res 77:3551–63
    [Google Scholar]
  78. 78. 
    Marchetti A, Felicioni L, Malatesta S et al. 2011. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J. Clin. Oncol. 29:3574–79
    [Google Scholar]
  79. 79. 
    Cardarella S, Ogino A, Nishino M et al. 2013. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin. Cancer Res. 19:4532–40
    [Google Scholar]
  80. 80. 
    Planchard D, Kim TM, Mazieres J et al. 2016. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 17:642–50
    [Google Scholar]
  81. 81. 
    Planchard D, Smit EF, Groen HJM et al. 2017. 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 18:1307–16
    [Google Scholar]
  82. 82. 
    Drilon A, Laetsch TW, Kummar S et al. 2018. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378:731–39
    [Google Scholar]
  83. 83. 
    Okamura R, Boichard A, Kato S et al. 2018. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis. Oncol https://doi.org/10.1200/PO.18.00183
    [Crossref] [Google Scholar]
  84. 84. 
    Kong-Beltran M, Seshagiri S, Zha J et al. 2006. Somatic mutations lead to an oncogenic deletion of Met in lung cancer. Cancer Res 66:283–89
    [Google Scholar]
  85. 85. 
    Drilon A, Clark J, Weiss J et al. 2018. Updated antitumor activity of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer. J. Thorac. Oncol. 13:S348
    [Google Scholar]
  86. 86. 
    Schreiber RD, Old LJ, Smyth MJ 2011. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331:1565–70
    [Google Scholar]
  87. 87. 
    Borghaei H, Paz-Ares L, Horn L et al. 2015. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373:1627–39
    [Google Scholar]
  88. 88. 
    Brahmer J, Reckamp KL, Baas P et al. 2015. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373:123–35
    [Google Scholar]
  89. 89. 
    Herbst RS, Baas P, Kim DW et al. 2016. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540–50
    [Google Scholar]
  90. 90. 
    Rittmeyer A, Barlesi F, Waterkamp D et al. 2017. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389:255–65
    [Google Scholar]
  91. 91. 
    Tsao MS, Kerr KM, Kockx M et al. 2018. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J. Thorac. Oncol. 13:1302–11
    [Google Scholar]
  92. 92. 
    Reck M, Rodriguez-Abreu D, Robinson AG et al. 2016. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375:1823–33
    [Google Scholar]
  93. 93. 
    Mok TSK, Wu YL, Kudaba I et al. 2019. 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 393:181930
    [Google Scholar]
  94. 94. 
    Carbone DP, Reck M, Paz-Ares L et al. 2017. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376:2415–26
    [Google Scholar]
  95. 95. 
    Peters S, Creelan B, Hellmann MD et al. 2017. Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage IV or recurrent non-small cell lung cancer: an exploratory analysis of CheckMate 026. Cancer Res 77: CT082 (Abstr.)
    [Google Scholar]
  96. 96. 
    Gandhi L, Rodriguez-Abreu D, Gadgeel S et al. 2018. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378:2078–92
    [Google Scholar]
  97. 97. 
    Paz-Ares L, Luft A, Vicente D et al. 2018. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N. Engl. J. Med. 379:2040–51
    [Google Scholar]
  98. 98. 
    Socinski MA, Jotte RM, Cappuzzo F et al. 2018. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378:2288–301
    [Google Scholar]
  99. 99. 
    Hellmann MD, Ciuleanu TE, Pluzanski A et al. 2018. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378:2093–104
    [Google Scholar]
  100. 100. 
    Skoulidis F, Goldberg ME, Greenawalt DM et al. 2018. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 8:822–35
    [Google Scholar]
  101. 101. 
    Zaretsky JM, Garcia-Diaz A, Shin DS et al. 2016. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375:819–29
    [Google Scholar]
/content/journals/10.1146/annurev-med-051718-013524
Loading
/content/journals/10.1146/annurev-med-051718-013524
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error