Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Toward personalized treatment approaches for non-small-cell lung cancer

Nature Medicine volume 27, pages 1345–1356 (2021)Cite this article

Subjects

Abstract

Worldwide, lung cancer is the most common cause of cancer-related deaths. Molecular targeted therapies and immunotherapies for non-small-cell lung cancer (NSCLC) have improved outcomes markedly over the past two decades. However, the vast majority of advanced NSCLCs become resistant to current treatments and eventually progress. In this Perspective, we discuss some of the recent breakthrough therapies developed for NSCLC, focusing on immunotherapies and targeted therapies. We highlight our current understanding of mechanisms of resistance and the importance of incorporating genomic analyses into clinical studies to decipher these further. We underscore the future role of neoadjuvant and maintenance combination therapy approaches to potentially cure early disease. A major challenge to successful development of rational combination therapies will be the application of robust predictive biomarkers for clear-cut patient stratification, and we provide our views on clinical research areas that could influence how NSCLC will be managed over the coming decade.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Molecular landscape of NSCLC.
Fig. 2: Illustration of OS for targeted and immunochemotherapy approaches.
Fig. 3: Major mechanisms of secondary immune escape to ICBs.

Similar content being viewed by others

References

  1. World Health Organization. Cancer Fact Sheet. https://www.who.int/news-room/fact-sheets/detail/cancer (2018).

  2. Molina, J. R., Yang, P., Cassivi, S. D., Schild, S. E. & Adjei, A. A. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin. Proc. 83, 584–594 (2008).

    Article  PubMed  Google Scholar 

  3. Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446–454 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. Herbst, R. S. et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J. Clin. Oncol. 20, 3815–3825 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Herbst, R. S. et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J. Clin. Oncol. 23, 5892–5899 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19, 39–56 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Gridelli, C. et al. Gefitinib as first-line treatment for patients with advanced non-small-cell lung cancer with activating epidermal growth factor receptor mutation: Review of the evidence. Lung Cancer 71, 249–257 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Ramalingam, S. S. et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N. Engl. J. Med. 382, 41–50 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Mok, T. et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann. Oncol. 31, 1056–1064 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Bar-Sagi, D., Knelson, E. H. & Sequist, L. V. A bright future for KRAS inhibitors. Nat. Cancer 1, 25–27 (2020).

    Article  PubMed  Google Scholar 

  11. Skoulidis, F. et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med. 384, 2371–2381 (2021).

  12. AACR Project GENIE consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov. 7, 818–831 (2017).

  13. Scagliotti, G. V. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Gadgeel, S. et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 38, 1505–1517 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Paz-Ares, L. et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N. Engl. J. Med. 379, 2040–2051 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Gettinger, S. et al. Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 Study. J. Clin. Oncol. 36, 1675–1684 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Garon, E. B. et al. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J. Clin. Oncol. 37, 2518–2527 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gibney, G. T., Weiner, L. M. & Atkins, M. B. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 17, e542–e551 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sanmamed, M. F. & Chen, L. A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell 175, 313–326 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Rousseau, B. et al. The spectrum of benefit from checkpoint blockade in hypermutated tumors. N. Engl. J. Med. 384, 1168–1170 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Marabelle, A. et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21, 1353–1365 (2020).

    Article  CAS  PubMed  Google Scholar 

  28. Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545, 446–451 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chaudhuri, A. A. et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov. 7, 1394–1403 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shen, S. Y. et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature 563, 579–583 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Baruch, E. N. et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 371, 602–609 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Chin, E. N. et al. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. Science 369, 993–999 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405–413 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Sharma, P. et al. The next decade of immune checkpoint therapy. Cancer Discov. 11, 838–857 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Paz-Ares, L. et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 22, 198–211 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Boyer, M. et al. Pembrolizumab plus ipilimumab or placebo for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%: randomized, double-blind phase III KEYNOTE-598 study. J. Clin. Oncol. Jco2003579 (2021).

  42. Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Manieri, N. A., Chiang, E. Y. & Grogan, J. L. TIGIT: a key inhibitor of the cancer immunity cycle. Trends Immunol. 38, 20–28 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Chauvin, J. M. et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J. Clin. Invest. 125, 2046–2058 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Ahn, M. et al. 1400P - Vibostolimab, an anti-TIGIT antibody, as monotherapy and in combination with pembrolizumab in anti-PD-1/PD-L1-refractory NSCLC. Ann. Oncol. 31, S754–S840 (2020).

    Google Scholar 

  49. Rodriguez-Abreu, D. et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J. Clin. Oncol. 38, 9503–9503 (2020).

    Article  Google Scholar 

  50. Lipson, E. J. et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J. Clin. Oncol. 39, abstr. 9503 (2021).

    Article  Google Scholar 

  51. Rosenberg, S. A., Yang, J. C., White, D. E. & Steinberg, S. M. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann. Surg. 228, 307–319 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rosenberg, S. A. IL-2: the first effective immunotherapy for human cancer. J. Immunol. 192, 5451–5458 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Abbas, A. K., Trotta, E., D, R. S., Marson, A. & Bluestone, J. A. Revisiting IL-2: biology and therapeutic prospects. Sci. Immunol. 3, eaat1482 (2018).

    Article  PubMed  Google Scholar 

  54. Chen, X. et al. A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2. Cell Death Dis. 9, 989 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Jiao, X. D. et al. The prognostic value of tumor mutation burden in EGFR-mutant advanced lung adenocarcinoma, an analysis based on cBioPortal data base. J. Thorac. Dis. 11, 4507–4515 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Spigel, D. R. et al. Total mutation burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies. J. Clin. Oncol. 34, 9017 (2016).

    Article  Google Scholar 

  57. Reck, M. et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir. Med. 7, 387–401 (2019).

    Article  CAS  PubMed  Google Scholar 

  58. Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Koyama, S. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cully, M., You, H., Levine, A. J. & Mak, T. W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer 6, 184–192 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. George, S. et al. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity 46, 197–204 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Redman, M. W. et al. Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol. Lancet Oncol. 21, 1589–1601 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Langer, C. J. et al. SWOG S1400B (NCT02785913), a phase II study of GDC-0032 (Taselisib) for previously treated PI3K-positive patients with stage IV squamous cell lung cancer (Lung-MAP Sub-Study). J. Thorac. Oncol. 14, 1839–1846 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Vidotto, T. et al. Emerging role of PTEN loss in evasion of the immune response to tumours. Br. J. Cancer 122, 1732–1743 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hegde, P. S., Wallin, J. J. & Mancao, C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin. Cancer Biol. 52, 117–124 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Oyama, T. et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J. Immunol. 160, 1224–1232 (1998).

    CAS  PubMed  Google Scholar 

  68. Crispe, I. N. Immune tolerance in liver disease. Hepatology 60, 2109–2117 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Lee, J. C. et al. Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis. Sci. Immunol. 5, eaba0759 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tumeh, P. C. et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol. Res 5, 417–424 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pao, W. et al. Tissue-specific immunoregulation: a call for better understanding of the “Immunostat” in the context of cancer. Cancer Discov. 8, 395–402 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Shen, Y. et al. Reduction of liver metastasis stiffness improves response to bevacizumab in metastatic colorectal cancer. Cancer Cell 37, 800–817.e807 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. Taylor, M. H. et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J. Clin. Oncol. 38, 1154–1163 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Neal, J. W. et al. Cabozantinib in combination with atezolizumab in non-small cell lung cancer (NSCLC) patients previously treated with an immune checkpoint inhibitor: results from cohort 7 of the COSMIC-021 study. J. Clin. Oncol. 38, 9610–9610 (2020).

    Article  Google Scholar 

  75. Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nat. Med. 26, 1733–1741 (2020).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Schaaf, M. B., Garg, A. D. & Agostinis, P. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy. Cell Death Dis. 9, 115 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Pignon, J. P. et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J. Clin. Oncol. 26, 3552–3559 (2008).

    Article  PubMed  Google Scholar 

  79. Detterbeck, F. C., Boffa, D. J., Kim, A. W. & Tanoue, L. T. The eighth edition lung cancer stage classification. Chest 151, 193–203 (2017).

    Article  PubMed  Google Scholar 

  80. Pechoux, C. L. et al. An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: primary end-point analysis of LungART (IFCT-0503, UK NCRI, SAKK) NCT00410683. Ann. Oncol. 31, S1142–S1215 (2020).

    Article  Google Scholar 

  81. Zhong, W. Z. et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 19, 139–148 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Wu, Y. L. et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 383, 1711–1723 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Jones, G. D. et al. KRAS (G12C) mutation is associated with increased risk of recurrence in surgically resected lung adenocarcinoma. Clin. Cancer Res. 27, 2604–2612 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Antonia, S. J. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Spigel, D. R. et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial. J. Clin. Oncol. 39, 8511–8511 (2021).

    Article  Google Scholar 

  86. Roche. Pivotal phase III study shows Roche’s Tecentriq helped people with early lung cancer live longer without their disease returning. https://www.roche.com/media/releases/med-cor-2021-03-22.htm (2021).

  87. Forde, P. M. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 378, 1976–1986 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bristol Myers Squibb. Neoadjuvant Opdivo (nivolumab) plus chemotherapy significantly improves pathologic complete response in patients with resectable non-small cell lung cancer in phase 3 CheckMate -816 trial. https://news.bms.com/news/corporate-financial/2021/Neoadjuvant-Opdivo-nivolumab-Plus-Chemotherapy-Significantly-Improves-Pathologic-Complete-Response-in-Patients-with-Resectable-Non-Small-Cell-Lung-Cancer-in-Phase-3-CheckMate--816-Trial/default.aspx (2021).

  89. Cascone, T. et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat. Med. 27, 504–514 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shu, C. A. et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 21, 786–795 (2020).

    Article  CAS  PubMed  Google Scholar 

  91. Tanaka, N. et al. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-21-0365 (2021).

  92. Corcoran, R. B. & Chabner, B. A. Application of cell-free DNA analysis to cancer treatment. N. Engl. J. Med. 379, 1754–1765 (2018).

    Article  CAS  PubMed  Google Scholar 

  93. Spreafico, A., Hansen, A. R., Abdul Razak, A. R., Bedard, P. L. & Siu, L. L. The future of clinical trial design in oncology. Cancer Discov. 11, 822–837 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rotow, J. & Bivona, T. G. Understanding and targeting resistance mechanisms in NSCLC. Nat. Rev. Cancer 17, 637–658 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Hutchison, D. J. Cross resistance and collateral sensitivity studies in cancer chemotherapy. Adv. Cancer Res. 7, 235–250 (1963).

    Article  CAS  PubMed  Google Scholar 

  96. Shah, K. N. et al. Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer. Nat. Med. 25, 111–118 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Schoenfeld, A. J. & Yu, H. A. The evolving landscape of resistance to osimertinib. J. Thorac. Oncol. 15, 18–21 (2020).

    Article  PubMed  Google Scholar 

  98. Kim, J. M. & Chen, D. S. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann. Oncol. 27, 1492–1504 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Coussens, L. M., Zitvogel, L. & Palucka, A. K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Anagnostou, V. et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 7, 264–276 (2017).

    Article  CAS  PubMed  Google Scholar 

  106. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang, T. T. et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway. Gut 66, 1900–1911 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949.e916 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271.e1211 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gettinger, S. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Dhatchinamoorthy, K., Colbert, J. D. & Rock, K. L. Cancer immune evasion through loss of MHC class I antigen presentation. Front Immunol. 12, 636568 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sade-Feldman, M. et al. Defining T Cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e1020 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dongre, A. et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res. 77, 3982–3989 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Sistigu, A., Di Modugno, F., Manic, G. & Nisticò, P. Deciphering the loop of epithelial-mesenchymal transition, inflammatory cytokines and cancer immunoediting. Cytokine Growth Factor Rev. 36, 67–77 (2017).

    Article  CAS  PubMed  Google Scholar 

  119. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Joshi, K. et al. Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer. Nat. Med. 25, 1549–1559 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Shaw, A. T. et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann. Oncol. 30, 1121–1126 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Drilon, A. et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat. Med. 26, 47–51 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Herbst, R. S. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Middleton, G. et al. The National Lung Matrix Trial of personalized therapy in lung cancer. Nature 583, 807–812 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Step 1 of the ctDNA to Monitor Treatment Response (ctMoniTR) project (Friends of Cancer Research, 2020); https://friendsofcancerresearch.org/ctdna

  127. Blackburn, E. H. Cancer interception. Cancer Prev. Res. (Phila.) 4, 787–792 (2011).

    Article  CAS  Google Scholar 

  128. Janssen Pharmaceutical Companies. New amivantamab data from CHRYSALIS study show robust clinical activity and durable responses in patients with metastatic or unresectable non-small cell lung cancer and EGFR exon 20 insertion mutations (Cision, 2021); https://www.prnewswire.com/news-releases/new-amivantamab-data-from-chrysalis-study-show-robust-clinical-activity-and-durable-responses-in-patients-with-metastatic-or-unresectable-non-small-cell-lung-cancer-and-egfr-exon-20-insertion-mutations-301217851.html

  129. Vasan, N., Baselga, J. & Hyman, D. M. A view on drug resistance in cancer. Nature 575, 299–309 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Palmer, A. C. & Sorger, P. K. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy. Cell 171, 1678–1691.e1613 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Settleman, J., Neto, J. M. F. & Bernards, R. Thinking differently about cancer treatment regimens. Cancer Discov. 11, 1016–1023 (2021).

    Article  PubMed  Google Scholar 

  132. Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin. 71, 7–33 (2021).

    Article  PubMed  Google Scholar 

  133. Sabari, J. K. et al. OA04.04 Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer. J. Thorac. Oncol. 16, S108–S109 (2021). suppl.

    Article  Google Scholar 

  134. Wolf, J. et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N. Engl. J. Med. 383, 944–957 (2020).

    Article  CAS  PubMed  Google Scholar 

  135. Paik, P. K. et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N. Engl. J. Med. 383, 931–943 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Shaw, A. T. et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N. Engl. J. Med. 383, 2018–2029 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Camidge, D. R. et al. Brigatinib versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. J. Clin. Oncol. 38, 3592–3603 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  139. Drilon, A. et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N. Engl. J. Med. 383, 813–824 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Shaw, A. T. et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 20, 1691–1701 (2019).

    Article  CAS  PubMed  Google Scholar 

  141. Drilon, A. et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 21, 261–270 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Planchard, D. 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. 18, 1307–1316 (2017).

    Article  CAS  PubMed  Google Scholar 

  143. Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).

    Article  CAS  PubMed  Google Scholar 

  144. Mok, T. S. K. 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 393, 1819–1830 (2019).

    Article  CAS  PubMed  Google Scholar 

  145. Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).

    Article  CAS  PubMed  Google Scholar 

  146. Goldberg, S. B. et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 21, 655–663 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  148. Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).

    Article  CAS  PubMed  Google Scholar 

  149. West, H. 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. 20, 924–937 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Herbst, R. S. et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N. Engl. J. Med. 383, 1328–1339 (2020).

    Article  CAS  PubMed  Google Scholar 

  151. Sezer, A. et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 397, 592–604 (2021).

    Article  CAS  PubMed  Google Scholar 

  152. Li, T., Kung, H. J., Mack, P. C. & Gandara, D. R. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J. Clin. Oncol. 31, 1039–1049 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Collisson, E. A. et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

    Article  CAS  Google Scholar 

  154. Drilon, A., Cappuzzo, F., Ou, S. I. & Camidge, D. R. Targeting MET in lung cancer: will expectations finally be MET? J. Thorac. Oncol. 12, 15–26 (2017).

    Article  PubMed  Google Scholar 

  155. Awad, M. M. et al. Long-term overall survival from KEYNOTE-021 cohort G: pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous NSCLC. J. Thorac. Oncol. 16, 162–168 (2021).

    Article  CAS  PubMed  Google Scholar 

  156. Paz-Ares, L. et al. A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: protocol-specified final analysis of KEYNOTE-407. J. Thorac. Oncol. 15, 1657–1669 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Thommen, D. S. et al. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24, 994–1004 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Meina Wang, Roy S. Herbst & Chris Boshoff

  2. Pfizer Inc., New York City, NY, USA

    Chris Boshoff

Authors
  1. Meina Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roy S. Herbst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chris Boshoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.W., R.S.H. and C.B. conceived, wrote and edited this review.

Corresponding authors

Correspondence to Roy S. Herbst or Chris Boshoff.

Ethics declarations

Competing interests

R.S.H. receives consulting fees from Abbvie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals, Bolt Biotherapeutics, Bristol-Myers Squibb, Candel Therapeutics, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly and Company, EMD Serono, Foundation Medicine, Genentech and Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Merck, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Oncternal Therapeutics, Pfizer, Refactor Health, Ribbon Therapeutics, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCubePharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen, Ventana Medical Systems, WindMIL Therapeutics, Xencor. R.S.H. also receives research support from AstraZeneca, Eli Lilly and Company, Genentech and Roche, and Merck, and serves as a board member (non-executive, independent member) for Immunocore Holdings and Junshi Pharmaceuticals. C.B. is an employee and shareholder of Pfizer. M.W. declares no competing interests.

Additional information

Peer review information Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Karen O’Leary was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, M., Herbst, R.S. & Boshoff, C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med 27, 1345–1356 (2021). https://doi.org/10.1038/s41591-021-01450-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-021-01450-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research