Review Article | Published:

The biology and management of non-small cell lung cancer

Nature volume 553, pages 446454 (25 January 2018) | Download Citation

Abstract

Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015)

  2. 2.

    , , , & Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin. Proc. 83, 584–594 (2008)

  3. 3.

    , , , & Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143, e1S–e29S (2013)

  4. 4.

    , & Lung cancer in never smokers--a different disease. Nat. Rev. Cancer 7, 778–790 (2007)

  5. 5.

    et al. Environmental tobacco smoke and risk of respiratory cancer and chronic obstructive pulmonary disease in former smokers and never smokers in the EPIC prospective study. Br. Med. J. 330, 277 (2005)

  6. 6.

    , & The accumulated evidence on lung cancer and environmental tobacco smoke. Br. Med. J. 315, 980–988 (1997)

  7. 7.

    et al. Nicotine, carcinogen, and toxin exposure in long-term e-cigarette and nicotine replacement therapy users: a cross-sectional study. Ann. Intern. Med. 166, 390–400 (2017)

  8. 8.

    & Varenicline for tobacco dependence. N. Engl. J. Med. 359, 2018–2024 (2008)

  9. 9.

    et al. Electronic nicotine delivery systems: a policy statement from the American Association for Cancer Research and the American Society of Clinical Oncology. J. Clin. Oncol. 33, 952–963 (2015)

  10. 10.

    et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256–259 (2014)

  11. 11.

    et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007)

  12. 12.

    et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010)

  13. 13.

    et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2, e17 (2005)

  14. 14.

    et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008)

  15. 15.

    & Precision diagnosis and treatment for advanced non-small-cell lung cancer. N. Engl. J. Med. 377, 849–861 (2017)

  16. 16.

    et al. p53 mutations and survival in stage I non-small-cell lung cancer: results of a prospective study. J. Natl. Cancer Inst. 95, 961–970 (2003)

  17. 17.

    Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014)

  18. 18.

    et al. Integrative clinical genomics of metastatic cancer. Nature 548, 297–303 (2017)

  19. 19.

    et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016)

  20. 20.

    et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015)

  21. 21.

    et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 76, 999–1008 (2016)

  22. 22.

    Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012). References 17 and 22 are landmark genomics analyses that describe the molecular landscapes of lung adenocarcinoma and squamous cell carcinoma, respectively.

  23. 23.

    et al. Systemic therapy for stage IV non-small-cell lung cancer: american society of clinical oncology clinical practice guideline update. J. Clin. Oncol. 35, 3484–3515 (2017)

  24. 24.

    et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 346, 92–98 (2002)

  25. 25.

    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. 26, 3543–3551 (2008)

  26. 26.

    et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006)

  27. 27.

    et al. 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, 763–774 (2015)

  28. 28.

    et al. 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, 665–673 (2014)

  29. 29.

    et al. Lung cancer: current therapies and new targeted treatments. Lancet 389, 299–311 (2017)

  30. 30.

    et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 11, 39–51 (2016)

  31. 31.

    et al. Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non-small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario clinical practice guideline update. J. Clin. Oncol. 35, 2960–2974 (2017)

  32. 32.

    . et al. Robotic versus video-assisted lobectomy/segmentectomy for lung cancer: a meta-analysis. Ann. Surg. (2017)

  33. 33.

    , , , & Comparison of particle beam therapy and stereotactic body radiotherapy for early stage non-small cell lung cancer: A systematic review and hypothesis-generating meta-analysis. Radiother. Oncol. 123, 346–354 (2017)

  34. 34.

    et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N. Engl. J. Med. 323, 940–945 (1990)

  35. 35.

    et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J. Natl. Cancer Inst. 103, 1452–1460 (2011)

  36. 36.

    , & Lung cancer. N. Engl. J. Med. 359, 1367–1380 (2008)

  37. 37.

    , , & Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey. J. Thorac. Oncol. 5, 29–33 (2010)

  38. 38.

    et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J. Clin. Oncol. 21, 2237–2246 (2003)

  39. 39.

    et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. J. Am. Med. Assoc. 290, 2149–2158 (2003)

  40. 40.

    et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353, 123–132 (2005)

  41. 41.

    et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004)

  42. 42.

    . et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004). References 41 and 42 were among the first studies to demonstrate that EGFR mutations in NSCLC confer sensitivity to anti-EGFR tyrosine kinase inhibitors.

  43. 43.

    et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131, 1190–1203 (2007)

  44. 44.

    et al. FDA approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist 21, 634–642 (2016)

  45. 45.

    et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. J. Am. Med. Assoc. 311, 1998–2006 (2014)

  46. 46.

    , & The EGFR family: not so prototypical receptor tyrosine kinases. Cold Spring Harb. Perspect. Biol. 6, a020768 (2014)

  47. 47.

    , & Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat. Rev. Clin. Oncol. 7, 493–507 (2010)

  48. 48.

    , , & Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 7, 169–181 (2007)

  49. 49.

    . et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009)This study relates to a change in the era of personalized therapy, and demonstrates that an anti-EGFR tyrosine kinase inhibitor is superior to cytotoxic therapy in patients with tumours that contain an activating EGFR mutation.

  50. 50.

    et al. 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, 2866–2874 (2011)

  51. 51.

    et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010)

  52. 52.

    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. 11, 121–128 (2010)

  53. 53.

    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. 12, 735–742 (2011).

  54. 54.

    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. 13, 239–246 (2012)

  55. 55.

    et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann. Oncol. 28, 270–277 (2017)

  56. 56.

    et al. 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, 1454–1466 (2017)

  57. 57.

    et al. 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, 141–151 (2015)

  58. 58.

    et al. Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification. Cancer Res. 67, 2046–2053 (2007)

  59. 59.

    et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005)

  60. 60.

    et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011)

  61. 61.

    , & Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat. Rev. Clin. Oncol. 11, 473–481 (2014)

  62. 62.

    et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372, 1689–1699 (2015)

  63. 63.

    et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017)

  64. 64.

    et al. Osimertinib in untreated EGFR-mutated advanced non-small cell lung cancer. N. Engl. J. Med. (2017)

  65. 65.

    et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015)

  66. 66.

    et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin. Cancer Res. 21, 3924–3933 (2015)

  67. 67.

    et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534, 129–132 (2016)

  68. 68.

    et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat. Commun. 8, 14768 (2017)

  69. 69.

    , & Targeting ALK: precision medicine takes on drug resistance. Cancer Discov. 7, 137–155 (2017)

  70. 70.

    . et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007)This study describes the discovery of ALK rearrangements in NSCLC.

  71. 71.

    . et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010)This study is the first to report the activity of crizotinib in patients with ALK rearrangements.

  72. 72.

    et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013)

  73. 73.

    et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014)

  74. 74.

    et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, 1189–1197 (2014)

  75. 75.

    et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 17, 234–242 (2016)

  76. 76.

    et al. 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, 2490–2498 (2017)

  77. 77.

    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 389, 917–929 (2017)

  78. 78.

    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 390, 29–39 (2017)

  79. 79.

    et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017)

  80. 80.

    et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 6, 1118–1133 (2016)

  81. 81.

    et al. 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, 1590–1599 (2017)

  82. 82.

    et al. Oncogene addiction in non-small cell lung cancer: focus on ROS1 inhibition. Cancer Treat. Rev. 55, 83–95 (2017)

  83. 83.

    et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 371, 1963–1971 (2014)

  84. 84.

    et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring Ros1 rearrangement. J. Clin. Oncol. 35, 2613–2618 (2017)

  85. 85.

    et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N. Engl. J. Med. 368, 2395–2401 (2013)

  86. 86.

    et al. Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PLoS One 8, e82236 (2013)

  87. 87.

    et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J. Clin. Oncol. 29, 3574–3579 (2011)

  88. 88.

    et al. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin. Can. Res. 19, 4532–4540 (2013)

  89. 89.

    et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015)

  90. 90.

    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. 17, 642–650 (2016)

  91. 91.

    et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 17, 984–993 (2016)

  92. 92.

    et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015)

  93. 93.

    et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 5, 842–849 (2015)

  94. 94.

    et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J. Clin. Oncol. 34, 721–730 (2016)

  95. 95.

    et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J. Clin. Oncol. 31, 1997–2003 (2013)

  96. 96.

    et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann. Oncol. 27, 281–286 (2016)

  97. 97.

    et al. KIF5B-RET fusions in lung adenocarcinoma. Nat. Med. 18, 375–377 (2012)

  98. 98.

    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. 17, 1653–1660 (2016)

  99. 99.

    et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J. Clin. Oncol. 35, 1403–1410 (2017)

  100. 100.

    et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. J. Clin. Oncol. 35, LBA2501–LBA2501 (2017)

  101. 101.

    et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 7, 963–972 (2017)

  102. 102.

    The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin. Orthop. Relat. Res. (262):3–11 (1991)

  103. 103.

    , & Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996)

  104. 104.

    et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010)

  105. 105.

    et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002)

  106. 106.

    et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002)

  107. 107.

    et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012)

  108. 108.

    et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015)

  109. 109.

    et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014)

  110. 110.

    et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015)

  111. 111.

    . et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015). References 110 and 111 were the first phase 3 studies to show increased survival for ICBs compared to cytotoxic therapy in patients with previously treated advanced-stage NSCLC, heralding the era of immunotherapy for NSCLC.

  112. 112.

    et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016)

  113. 113.

    et al. 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, 255–265 (2017)

  114. 114.

    . et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016). This study provides evidence that in selected patients with high tumour expression of PD-L1, ICBs are more effective than cytotoxic therapy in the first-line setting.

  115. 115.

    et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017)

  116. 116.

    & Diminished but not dead: chemotherapy for the treatment of NSCLC. Lancet Oncol. 17, 1464–1465 (2016)

  117. 117.

    et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015)

  118. 118.

    , , & Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013)

  119. 119.

    et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 17, 1497–1508 (2016)

  120. 120.

    , , & PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010)

  121. 121.

    et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 18, 31–41 (2017)

  122. 122.

    , , & Primary, adaptive, and acquired resistance to cancer immunotherapy. Nat. Med. 23, 1362–1368 (2017)

  123. 123.

    et al. Combinatorial strategies for the induction of immunogenic cell death. Front. Immunol. 6, 187 (2015)

  124. 124.

    , , & Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 3, 841–849 (2017)

  125. 125.

    et al. Control of the immune response by pro-angiogenic factors. Front. Oncol. 4, 70 (2014)

  126. 126.

    et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017)

  127. 127.

    et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017)

  128. 128.

    et al. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov. 7, 1420–1435 (2017)

  129. 129.

    et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016)

  130. 130.

    , , , & Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210, 1389–1402 (2013)

  131. 131.

    et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017)

  132. 132.

    et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J. Clin. Oncol. 34, 3375–3382 (2016)

  133. 133.

    et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 1, 44–53 (2011)

  134. 134.

    et al. Lung Master Protocol (Lung-MAP)-A biomarker-driven protocol for accelerating development of therapies for squamous cell lung cancer: SWOG S1400. Clin. Cancer Res. 21, 1514–1524 (2015)

  135. 135.

    et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017)

  136. 136.

    . et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545, 446–451 (2017)This study introduces ctDNA profiling to track the subclonal nature of lung cancer progression, providing an approach for ctDNA-driven therapeutic studies.

  137. 137.

    . et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015). This is a landmark study indicating that lung cancers with high non-synonymous mutation burden are more responsive to ICB.

  138. 138.

    & Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017)

  139. 139.

    et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23, 1362–1368 (2017)

Download references

Acknowledgements

We would like to thank L. Chen and A. M. Incassati for editorial assistance. R. Herbst is supported by the Yale SPORE in Lung Cancer (P50CA196530).

Author information

Affiliations

  1. Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA

    • Roy S. Herbst
    •  & Chris Boshoff
  2. Washington University School of Medicine, St Louis, Missouri, USA

    • Daniel Morgensztern
  3. Pfizer, Inc. New York City, New York, USA

    • Chris Boshoff

Authors

  1. Search for Roy S. Herbst in:

  2. Search for Daniel Morgensztern in:

  3. Search for Chris Boshoff in:

Contributions

All authors contributed to the writing of this Review.

Competing interests

R.S.H. is a compensated advisor for Astra Zeneca, Lilly, Genentech/Roche, Pfizer and Merck (MSD). D.M. is a compensated advisor for Celgene, BMS and AbbVie. C.B. is an employee of Pfizer.

Corresponding authors

Correspondence to Roy S. Herbst or Chris Boshoff.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Table 1.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature25183

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.