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  • Review Article
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Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC

Nature Reviews Clinical Oncology volume 18, pages 625–644 (2021)Cite this article

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Abstract

The treatment landscape of driver-negative non-small-cell lung cancer (NSCLC) is rapidly evolving. Immune-checkpoint inhibitors, specifically those targeting PD-1 or PD-L1, have demonstrated durable efficacy in a subset of patients with NSCLC, and these agents have become the cornerstone of first-line therapy. Approved immunotherapeutic strategies for treatment-naive patients now include monotherapy, immunotherapy-exclusive regimens or chemotherapy–immunotherapy combinations. Decision making in this space is complex given the absence of head-to-head prospective comparisons, although a thorough analysis of long-term efficacy and safety data from pivotal clinical trials can provide insight into the optimal management of each subset of patients. Indeed, histological subtype and the extent of tumour cell PD-L1 expression are paramount to regimen selection, although other clinicopathological factors and patient preferences might also be relevant in certain scenarios. Finally, several emerging biomarkers and novel therapeutic strategies are currently under investigation, and these might further refine the current treatment paradigm. In this Review, we discuss the current treatment landscape and detail our approach to first-line immunotherapy regimen selection for patients with advanced-stage, driver-negative NSCLC.

Key points

  • For patients with advanced-stage NSCLC lacking a targetable driver alteration, anti-PD-1/PD-L1 antibodies are now the cornerstone of first-line therapy.

  • Anti-PD-1/PD-L1 antibody-containing regimens can be broadly classified as immunotherapy-exclusive or chemotherapy–immunotherapy combinations, although all therapies or regimens have received approval based on their superiority to platinum-doublet chemotherapy; head-to-head comparisons of efficacy are currently lacking.

  • Tumour cell PD-L1 expression remains the most robust clinical predictor of response to anti-PD-1/PD-L1 antibodies, although we envision the future integration of various other novel biomarkers for a more personalized approach to immunotherapy selection.

  • First-line anti-PD-1/PD-L1 antibodies as monotherapies are favoured for most patients with advanced-stage NSCLC with high levels of tumour cell PD-L1 expression (≥50%) that lack a targetable driver alteration.

  • For patients with low or absent PD-L1 expression, or those with high PD-L1 expression with an immediate need for cytoreduction, combination regimens containing anti-PD-1/PD-L1 antibodies plus histology-selected platinum-doublet chemotherapies are favoured.

  • Trials seeking to refine the existing treatment strategies and integrate novel therapies to enhance the efficacy of currently approved agents are currently ongoing.

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Fig. 1: Milestone overall survival outcomes for select immunotherapy-based regimens as first-line therapies for driver-negative NSCLC.
Fig. 2: Incidence of selected toxicities among patients receiving first-line immunotherapy-based regimens for advanced-stage NSCLC.
Fig. 3: Immunotherapy-based management of patients with advanced-stage driver-negative NSCLC.
Fig. 4: Existing and emerging therapeutic targets for NSCLC.

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References

  1. Jordan, E. J. et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhang, Y. et al. Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin. Cancer Res. 18, 1947–1953 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Steuer, C. E. et al. Role of race in oncogenic driver prevalence and outcomes in lung adenocarcinoma: results from the lung cancer mutation consortium. Cancer 122, 766–772 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Sacher, A. G. et al. Association between younger age and targetable genomic alterations and prognosis in non-small-cell lung cancer. JAMA Oncol. 2, 313–320 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Howlader, N. et al. The effect of advances in lung-cancer treatment on population mortality. N. Engl. J. Med. 383, 640–649 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lindeman, N. I. et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J. Thorac. Oncol. 8, 823–859 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Khozin, S. et al. U.S. Food and Drug Administration approval summary: erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. Oncologist 19, 774–779 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Yang, J. C. et al. 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, 830–838 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. Doebele, R. C. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1−2 trials. Lancet Oncol. 21, 271–282 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Drilon, A. et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N. Engl. J. Med. 378, 731–739 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hong, D. S. et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smit, E. F. et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J. Clin. Oncol. 38, 9504–9504 (2020).

    Article  Google Scholar 

  21. Riely, G. J. et al. 1261MO updated results from a phase I/II study of mobocertinib (TAK-788) in NSCLC with EGFR exon 20 insertions (exon20ins). Ann. Oncol. 31, S815–S816 (2020).

    Article  Google Scholar 

  22. Park, K. et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). J. Clin. Oncol. 38, 9512–9512 (2020).

    Article  Google Scholar 

  23. Kawaguchi, T. et al. Prospective analysis of oncogenic driver mutations and environmental factors: Japan molecular epidemiology for lung cancer study. J. Clin. Oncol. 34, 2247–2257 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Shi, Y. et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J. Thorac. Oncol. 9, 154–162 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dogan, S. et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin. Cancer Res. 18, 6169–6177 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, R. et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J. Clin. Oncol. 30, 4352–4359 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Shaw, A. T. & Solomon, B. Targeting anaplastic lymphoma kinase in lung cancer. Clin. Cancer Res. 17, 2081–2086 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Chia, P. L., Mitchell, P., Dobrovic, A. & John, T. Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin. Epidemiol. 6, 423–432 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Farago, A. F. et al. Clinicopathologic features of non-small-cell lung cancer harboring an NTRK gene fusion. JCO Precis. Oncol. https://doi.org/10.1200/PO.18.00037 (2018).

  30. Schrock, A. B. et al. Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations. J. Thorac. Oncol. 11, 1493–1502 (2016).

    Article  PubMed  Google Scholar 

  31. Digumarthy, S. R., Mendoza, D. P., Zhang, E. W., Lennerz, J. K. & Heist, R. S. Clinicopathologic and imaging features of non-small-cell lung cancer with MET exon 14 skipping mutations. Cancers 11, 2033 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  32. Villaruz, L. C. et al. Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium. Cancer 121, 448–456 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Mazieres, J. et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the immunotarget registry. Ann. Oncol. 30, 1321–1328 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hastings, K. et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Ann. Oncol. 30, 1311–1320 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gainor, J. F. et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin. Cancer Res. 22, 4585–4593 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dudnik, E. et al. Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC): outcomes with immune check-point inhibitors (ICPi). Lung Cancer 124, 117–124 (2018).

    Article  PubMed  Google Scholar 

  37. Bylicki, O. et al. Efficacy and safety of programmed cell-death-protein-1 and its ligand inhibitors in pretreated patients with epidermal growth-factor receptor-mutated or anaplastic lymphoma kinase-translocated lung adenocarcinoma. Medicine 99, e18726 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Guisier, F. et al. Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01-2018. J. Thorac. Oncol. 15, 628–636 (2020).

    Article  CAS  PubMed  Google Scholar 

  39. Dudnik, E. et al. BRAF mutant lung cancer: programmed death ligand 1 expression, tumor mutational burden, microsatellite instability status, and response to immune check-point inhibitors. J. Thorac. Oncol. 13, 1128–1137 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Grosse, A., Grosse, C., Rechsteiner, M. & Soltermann, A. Analysis of the frequency of oncogenic driver mutations and correlation with clinicopathological characteristics in patients with lung adenocarcinoma from northeastern Switzerland. Diagn. Pathol. 14, 18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Dang, A. H. et al. Actionable mutation profiles of non-small cell lung cancer patients from Vietnamese population. Sci. Rep. 10, 2707 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gou, L. Y. & Wu, Y. L. Prevalence of driver mutations in non-small-cell lung cancers in the People’s Republic of China. Lung Cancer 5, 1–9 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sholl, L. M. et al. Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the Lung Cancer Mutation Consortium experience. J. Thorac. Oncol. 10, 768–777 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kris, M. G. et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311, 1998–2006 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Kazandjian, D. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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 

  48. Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  50. Herbst, R. S. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Rittmeyer, A. 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).

    Article  PubMed  Google Scholar 

  52. Barlesi, F. et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol. 19, 1468–1479 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Antonia, S. J. et al. Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis. Lancet Oncol. 20, 1395–1408 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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 

  55. Reck, M. et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%. J. Clin. Oncol. https://doi.org/10.1200/JCO.21.00174 (2021).

  56. Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kerr, K. M. & Hirsch, F. R. Programmed death ligand-1 immunohistochemistry: friend or foe? Arch. Pathol. Lab. Med. 140, 326–331 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Garon, E. B. et al. Five-year overall survival for patients with advanced nonsmall-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 

  61. Herbst, R. S. et al. Long-term follow-up in the KEYNOTE-010 study of pembrolizumab (pembro) for advanced NSCLC, including in patients (pts) who completed 2 years of pembro and pts who received a second course of pembro. Ann. Oncol. 29, x42–x43 (2018).

    Article  Google Scholar 

  62. Herbst, R. S. et al. Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1positive, advanced nonsmall-cell lung cancer in the KEYNOTE-010 study. J. Clin. Oncol. 38, 1580–1590 (2020).

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. 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 

  65. Schoenfeld, A. J. et al. Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas. Ann. Oncol. 31, 599–608 (2020).

    Article  CAS  PubMed  Google Scholar 

  66. Taube, J. M. et al. Implications of the tumor immune microenvironment for staging and therapeutics. Mod. Pathol. 31, 214–234 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Cottrell, T. R. & Taube, J. M. PD-L1 and emerging biomarkers in immune checkpoint blockade therapy. Cancer J. 24, 41–46 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mansfield, A. S. et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann. Oncol. 27, 1953–1958 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kim, S. et al. Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas. Eur. J. Cancer 75, 141–149 (2017).

    Article  CAS  PubMed  Google Scholar 

  70. Uruga, H. et al. Programmed cell death ligand (PD-L1) expression in stage II and III lung adenocarcinomas and nodal metastases. J. Thorac. Oncol. 12, 458–466 (2017).

    Article  PubMed  Google Scholar 

  71. Munari, E. et al. PD-L1 expression heterogeneity in non-small cell lung cancer: defining criteria for harmonization between biopsy specimens and whole sections. J. Thorac. Oncol. 13, 1113–1120 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Camy, F. et al. Brain metastasis PD-L1 and CD8 expression is dependent on primary tumor type and its PD-L1 and CD8 status. J. Immunother. Cancer 8, e000597 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Rehman, J. A. et al. Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer. Mod. Pathol. 30, 340–349 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Midha, A. et al. PD-L1 expression in advanced NSCLC: primary lesions versus metastatic sites and impact of sample age. J. Clin. Oncol. 34, 3025–3025 (2016).

    Article  Google Scholar 

  75. Herbst, R. S. et al. Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial. Ann. Oncol. 30, 281–289 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hirsch, F. R. et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J. Thorac. Oncol. 12, 208–222 (2017).

    Article  PubMed  Google Scholar 

  77. Rimm, D. L. et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 3, 1051–1058 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Tsao, M. S. et al. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J. Thorac. Oncol. 13, 1302–1311 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ratcliffe, M. J. et al. Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein expression cutoffs in non-small cell lung cancer. Clin. Cancer Res. 23, 3585–3591 (2017).

    Article  CAS  PubMed  Google Scholar 

  80. Adam, J. et al. Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer. Ann. Oncol. 29, 953–958 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. 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 

  82. Hernandez, A. et al. Assessment of programmed death-ligand 1 (PD-L1) immunohistochemical expression on cytology specimens in non-small cell lung carcinoma. Am. J. Clin. Pathol. 151, 403–415 (2019).

    Article  CAS  PubMed  Google Scholar 

  83. Heymann, J. J. et al. PD-L1 expression in non-small cell lung carcinoma: comparison among cytology, small biopsy, and surgical resection specimens. Cancer Cytopathol. 125, 896–907 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Ilie, M. et al. Use of the 22C3 anti-programmed death-ligand 1 antibody to determine programmed death-ligand 1 expression in cytology samples obtained from non-small cell lung cancer patients. Cancer Cytopathol. 126, 264–274 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Noll, B. et al. Programmed death ligand 1 testing in non-small cell lung carcinoma cytology cell block and aspirate smear preparations. Cancer Cytopathol. 126, 342–352 (2018).

    Article  CAS  PubMed  Google Scholar 

  86. Sakata, K. K. et al. Comparison of programmed death ligand-1 immunohistochemical staining between endobronchial ultrasound transbronchial needle aspiration and resected lung cancer specimens. Chest 154, 827–837 (2018).

    Article  PubMed  Google Scholar 

  87. Skov, B. G. & Skov, T. Paired comparison of PD-L1 expression on cytologic and histologic specimens from malignancies in the lung assessed with PD-L1 IHC 28-8pharmDx and PD-L1 IHC 22C3pharmDx. Appl. Immunohistochem. Mol. Morphol. 25, 453–459 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Capizzi, E. et al. Validation of the immunohistochemical expression of programmed death ligand 1 (PD-L1) on cytological smears in advanced non small cell lung cancer. Lung Cancer 126, 9–14 (2018).

    Article  PubMed  Google Scholar 

  89. Munari, E. et al. Expression of programmed cell death ligand 1 in non-small cell lung cancer: comparison between cytologic smears, core biopsies, and whole sections using the SP263 assay. Cancer Cytopathol. 127, 52–61 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Zou, Y. et al. Cytology cell blocks from malignant pleural effusion are good candidates for PD-L1 detection in advanced NSCLC compared with matched histology samples. BMC Cancer 20, 344 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gosney, J. R., Boothman, A. M., Ratcliffe, M. & Kerr, K. M. Cytology for PD-L1 testing: a systematic review. Lung Cancer 141, 101–106 (2020).

    Article  PubMed  Google Scholar 

  92. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Mushti, S. L., Mulkey, F. & Sridhara, R. Evaluation of overall response rate and progression-free survival as potential surrogate endpoints for overall survival in immunotherapy trials. Clin. Cancer Res. 24, 2268–2275 (2018).

    Article  CAS  PubMed  Google Scholar 

  94. Mick, R. & Chen, T. T. Statistical challenges in the design of late-stage cancer immunotherapy studies. Cancer Immunol. Res. 3, 1292–1298 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Anagnostou, V. et al. Immuno-oncology trial endpoints: capturing clinically meaningful activity. Clin. Cancer Res. 23, 4959–4969 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Chen, T. T. Milestone survival: a potential intermediate endpoint for immune checkpoint inhibitors. J. Natl Cancer Inst. 107, djv156 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Roach, C. et al. Development of a companion diagnostic PD-L1 immunohistochemistry assay for pembrolizumab therapy in non-small-cell lung cancer. Appl. Immunohistochem. Mol. Morphol. 24, 392–397 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Vennapusa, B. et al. Development of a PD-L1 complementary diagnostic immunohistochemistry assay (SP142) for atezolizumab. Appl. Immunohistochem. Mol. Morphol. 27, 92–100 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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 

  100. Lopes, G. et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. J. Clin. Oncol. 36, LBA4 (2018).

    Article  Google Scholar 

  101. Brahmer, J. R. et al. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 18, 1600–1609 (2017).

    Article  CAS  PubMed  Google Scholar 

  102. Reck, M. et al. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur. J. Cancer 102, 23–30 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Reck, M. et al. Impact of nivolumab versus docetaxel on health-related quality of life and symptoms in patients with advanced squamous non-small cell lung cancer: results from the CheckMate 017 Study. J. Thorac. Oncol. 13, 194–204 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Barlesi, F. et al. Health-related quality of life in KEYNOTE-010: a phase II/III study of pembrolizumab versus docetaxel in patients with previously treated advanced, programmed death ligand 1-expressing NSCLC. J. Thorac. Oncol. 14, 793–801 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. 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 

  106. Rizvi, N. A. et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 6, 661–674 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Ferrara, R. et al. Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer. Cochrane Database Syst. Rev. 12, CD013257 (2020).

    PubMed  Google Scholar 

  108. Champiat, S. et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat. Rev. Clin. Oncol. 15, 748–762 (2018).

    Article  CAS  PubMed  Google Scholar 

  109. Kim, Y. et al. Hyperprogression after immunotherapy: clinical implication and genomic alterations in advanced non-small cell lung cancer patients (NSCLC). J. Clin. Oncol. 36, 9075 (2018).

    Article  Google Scholar 

  110. Ferrara, R. et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol. 4, 1543–1552 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Arasanz, H. et al. Early detection of hyperprogressive disease in non-small cell lung cancer by monitoring of systemic T cell dynamics. Cancers 12, 344 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  112. Kato, S. et al. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin. Cancer Res. 23, 4242–4250 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kim, C. G. et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann. Oncol. 30, 1104–1113 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Ferrara, R. et al. 1278P hyperprogressive disease (HPD) upon first-line PD-1/PD-L1 inhibitors (ICI) as single agent or in combination with platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients (pts). Ann. Oncol. 31, S826 (2020).

    Article  Google Scholar 

  115. 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 

  116. Rodríguez-Abreu, D. et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann. Oncol. https://doi.org/10.1016/j.annonc.2021.04.008 (2021).

  117. 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 

  118. 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 

  119. 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 

  120. Paz-Ares, L. et al. LBA3 nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (aNSCLC): CheckMate 227 — part 2 final analysis. Ann. Oncol. 30 (Suppl. 11), XI67−XI68 (2019).

    Google Scholar 

  121. Nishio, M. et al. Atezolizumab plus chemotherapy for first-line treatment of non-squamous non-small cell lung cancer: results from the randomized phase III IMpower132 trial. J. Thorac. Oncol. 16, 653–664 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Jotte, R. et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J. Thorac. Oncol. 15, 1351–1360 (2020).

    Article  CAS  PubMed  Google Scholar 

  123. Zhou, C. et al. LBA4 GEMSTONE-302: a phase III study of platinum-based chemotherapy (chemo) with placebo or CS1001, an anti-PDL1 antibody, for first-line (1L) advanced non-small cell lung cancer (NSCLC). Ann. Oncol. 31, S1386 (2020).

    Article  Google Scholar 

  124. Yang, Y. et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J. Thorac. Oncol. 15, 1636–1646 (2020).

    Article  CAS  PubMed  Google Scholar 

  125. 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 

  126. Krummel, M. F. & Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).

    Article  CAS  PubMed  Google Scholar 

  127. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Das, R. et al. Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo. J. Immunol. 194, 950–959 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Hellmann, M. D. 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).

    Article  CAS  PubMed  Google Scholar 

  130. 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 

  131. Ramalingam, S. S. et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: three-year update from CheckMate 227 part 1. J. Clin. Oncol. 38, 9500 (2020).

    Article  Google Scholar 

  132. Hellmann, M. D. et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33, 843–852 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ready, N. et al. First-line nivolumab plus ipilimumab in advanced non-small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. J. Clin. Oncol. 37, 992–1000 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 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 

  135. Lebbe, C. et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J. Clin. Oncol. 37, 867–875 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Reck, M. et al. Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. Eur. J. Cancer 116, 137–147 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. 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. https://doi.org/10.1200/JCO.20.03579 (2021).

  139. 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 

  140. AstraZeneca. Imfinzi and Imfinzi plus tremelimumab delayed disease progression in Phase III POSEIDON trial for 1st-line treatment of Stage IV non-small cell lung cancer. AstraZeneca Press Releases https://www.astrazeneca.com/media-centre/press-releases/2019/imfinzi-and-imfinzi-plus-tremelimumab-delayed-disease-progression-in-phase-iii-poseidon-trial-for-1st-line-treatment-of-stage-iv-non-small-cell-lung-cancer.html (2019).

  141. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. 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 

  143. 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 

  144. Socinski, M. A. et al. Abstract CT216: IMpower150 final analysis: efficacy of atezolizumab (atezo) + bevacizumab (bev) and chemotherapy in first-line (1L) metastatic nonsquamous (nsq) non-small cell lung cancer (NSCLC) across key subgroups. Cancer Res. 80, CT216 (2020).

    Google Scholar 

  145. Reck, M. et al. Safety and patient-reported outcomes of atezolizumab plus chemotherapy with or without bevacizumab versus bevacizumab plus chemotherapy in non-small-cell lung cancer. J. Clin. Oncol. 38, 2530–2542 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Owoyemi, I. et al. Clinical outcomes of solid organ transplant recipients with metastatic cancers who are treated with immune checkpoint inhibitors: a single-center analysis. Cancer 126, 4780–4787 (2020).

    Article  PubMed  Google Scholar 

  147. Kumar, V. et al. The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature. Oncologist 25, 505–514 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Haanen, J. et al. Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy. Ann. Oncol. 31, 724–744 (2020).

    Article  CAS  PubMed  Google Scholar 

  149. 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 

  150. Reck, M. et al. OA14.01 KEYNOTE-024 3-year survival update: pembrolizumab vs platinum-based chemotherapy for advanced non-small-cell lung cancer. J. Thorac. Oncol. 14, S243 (2019).

    Article  Google Scholar 

  151. Alberg, A. J., Brock, M. V., Ford, J. G., Samet, J. M. & Spivack, S. D. Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143 (Suppl. 5), e1S–e29S (2013).

    Article  Google Scholar 

  152. Govindan, R. et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150, 1121–1134 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 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 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Hellmann, M. D. et al. 1229PD — smoking history and response to nivolumab in patients with advanced Nsclcs. Ann. Oncol. 25, iv429 (2014).

    Article  Google Scholar 

  157. Gettinger, S. N. et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 33, 2004–2012 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Borghaei, H. et al. Pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer without tumor PD-L1 expression: a pooled analysis of 3 randomized controlled trials. Cancer 126, 4867–4877 (2020).

    Article  CAS  PubMed  Google Scholar 

  162. Gainor, J. F. et al. Clinical activity of programmed cell death 1 (PD-1) blockade in never, light, and heavy smokers with non-small-cell lung cancer and PD-L1 expression ≥50. Ann. Oncol. 31, 404–411 (2020).

    Article  CAS  PubMed  Google Scholar 

  163. Nosaki, K. et al. Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies. Lung Cancer 135, 188–195 (2019).

    Article  PubMed  Google Scholar 

  164. Passaro, A., Spitaleri, G., Gyawali, B. & de Marinis, F. Immunotherapy in non-small-cell lung cancer patients with performance status 2: clinical decision making with scant evidence. J. Clin. Oncol. 37, 1863–1867 (2019).

    Article  CAS  PubMed  Google Scholar 

  165. Su, C., Zhou, F., Shen, J., Zhao, J. & O’Brien, M. Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced non-small cell lung cancer without epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations — still a daily challenge. Eur. J. Cancer 83, 266–278 (2017).

    Article  CAS  PubMed  Google Scholar 

  166. Friedlaender, A., Banna, G. L., Buffoni, L. & Addeo, A. Poor-performance status assessment of patients with non-small cell lung cancer remains vague and blurred in the immunotherapy era. Curr. Oncol. Rep. 21, 107 (2019).

    Article  PubMed  Google Scholar 

  167. Waqar, S. N. et al. Non-small-cell lung cancer with brain metastasis at presentation. Clin. Lung Cancer 19, e373–e379 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Lukas, R. V. et al. Safety and efficacy analyses of atezolizumab in advanced non-small cell lung cancer (NSCLC) patients with or without baseline brain metastases. Ann. Oncol. 28, ii28 (2017).

    Article  Google Scholar 

  169. Hendriks, L. E. L. et al. Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors. J. Thorac. Oncol. 14, 1244–1254 (2019).

    Article  CAS  PubMed  Google Scholar 

  170. Mansfield, A. S. et al. 14820 — outcomes with pembrolizumab (pembro) monotherapy in patients (pts) with PD-L1-positive NSCLC with brain metastases: pooled analysis of KEYNOTE-001, -010, -024, and -042. Ann. Oncol. 30 (Suppl. 5), v602–v660 (2019).

    Article  Google Scholar 

  171. Prasad, V. & Kaestner, V. Nivolumab and pembrolizumab: monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Semin. Oncol. 44, 132–135 (2017).

    Article  CAS  PubMed  Google Scholar 

  172. Markham, A. Atezolizumab: first global approval. Drugs 76, 1227–1232 (2016).

    Article  CAS  PubMed  Google Scholar 

  173. Waterhouse, D. M. et al. Continuous versus 1-year fixed-duration nivolumab in previously treated advanced non-small-cell lung cancer: CheckMate 153. J. Clin. Oncol. 38, 3863–3873 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Herbst, R. et al. FP13.01 5-year survival update from KEYNOTE-010: pembrolizumab versus docetaxel in previously treated, PD-L1–positive advanced NSCLC. J. Thorac. Oncol. 16, S223−S224 (2021).

  175. Cho, B. C. et al. FP13.04 KEYNOTE-042 3-year survival update: 1L pembrolizumab vs platinum-based chemotherapy for PD-L1+ locally advanced/metastatic NSCLC. J. Thorac. Oncol. 16, S225−S226 (2021).

  176. Kowanetz, M. et al. OA20.01 tumor mutation burden (TMB) is associated with improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. J. Thorac. Oncol. 12, S321–S322 (2017).

    Article  Google Scholar 

  177. Herbst, R. S. et al. Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials. Ann. Oncol. 30, v916–v917 (2019).

    Article  Google Scholar 

  178. Owada-Ozaki, Y. et al. Prognostic impact of tumor mutation burden in patients with completely resected non-small cell lung cancer: brief report. J. Thorac. Oncol. 13, 1217–1221 (2018).

    Article  CAS  PubMed  Google Scholar 

  179. Valero, C. et al. The association between tumor mutational burden and prognosis is dependent on treatment context. Nat. Genet. 53, 11–15 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Rizvi, H. et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J. Clin. Oncol. 36, 633–641 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Lee, C. H., Yelensky, R., Jooss, K. & Chan, T. A. Update on tumor neoantigens and their utility: why it is good to be different. Trends Immunol. 39, 536–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 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 

  183. Ghorani, E. et al. Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma. Ann. Oncol. 29, 271–279 (2018).

    Article  CAS  PubMed  Google Scholar 

  184. Rech, A. J. et al. Tumor immunity and survival as a function of alternative neopeptides in human cancer. Cancer Immunol. Res. 6, 276–287 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Luksza, M. et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Kim, S. et al. Neopepsee: accurate genome-level prediction of neoantigens by harnessing sequence and amino acid immunogenicity information. Ann. Oncol. 29, 1030–1036 (2018).

    Article  CAS  PubMed  Google Scholar 

  187. Torralvo, J., Friedlaender, A., Achard, V. & Addeo, A. The activity of immune checkpoint inhibition in KRAS mutated non-small cell lung cancer: a single centre experience. Cancer Genomics Proteomics 16, 577–582 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Kim, J. H., Kim, H. S. & Kim, B. J. Prognostic value of KRAS mutation in advanced non-small-cell lung cancer treated with immune checkpoint inhibitors: a meta-analysis and review. Oncotarget 8, 48248–48252 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Gadgeel, S. M. et al. Abstract LB-397: pembrolizumab plus pemetrexed and platinum vs placebo plus pemetrexed and platinum as first-line therapy for metastatic nonsquamous NSCLC: analysis of KEYNOTE-189 by STK11 and KEAP1 status. Cancer Res. 80, LB-397 (2020).

    Google Scholar 

  190. Cho, B. C. et al. Abstract CT084: relationship between STK11 and KEAP1 mutational status and efficacy in KEYNOTE-042: pembrolizumab monotherapy versus platinum-based chemotherapy as first-line therapy for PD-L1-positive advanced NSCLC. Cancer Res. 80, CT084 (2020).

    Google Scholar 

  191. Rizvi, N. et al. OA04.07 mutations associated with sensitivity or resistance to immunotherapy in mNSCLC: analysis from the MYSTIC trial. J. Thorac. Oncol. 14, S217 (2019).

    Article  Google Scholar 

  192. 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 

  193. Ricciuti, B. et al. Diminished efficacy of PD-(L)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is impacted by KRAS mutation status. Presented at IASLC World Conference of Lung Cancer 2020 (IASLC, 2021).

  194. West, H. et al. 1265P IMpower150: a post hoc analysis of efficacy outcomes in patients with KRAS, STK11 and KEAP1 mutations. Ann. Oncol. 31, S817–S818 (2020).

    Article  Google Scholar 

  195. Chowell, D. et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359, 582–587 (2018).

    Article  CAS  PubMed  Google Scholar 

  196. Kvistborg, P. & Yewdell, J. W. Enhancing responses to cancer immunotherapy. Science 359, 516–517 (2018).

    Article  CAS  PubMed  Google Scholar 

  197. Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. 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 

  201. Zappasodi, R. et al. Non-conventional inhibitory CD4+Foxp3–PD-1hi T cells as a biomarker of immune checkpoint blockade activity. Cancer Cell 33, 1017−1032 (2018).

    Google Scholar 

  202. Fumet, J. D. et al. Prognostic and predictive role of CD8 and PD-L1 determination in lung tumor tissue of patients under anti-PD-1 therapy. Br. J. Cancer 119, 950–960 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Gettinger, S. N. et al. A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers. Nat. Commun. 9, 3196 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Han, J. et al. TCR repertoire diversity of peripheral PD-1+CD8+ T cells predicts clinical outcomes after immunotherapy in patients with non-small cell lung cancer. Cancer Immunol. Res. 8, 146–154 (2020).

    Article  CAS  PubMed  Google Scholar 

  205. Datar, I. et al. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin. Cancer Res. 25, 4663–4673 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Liu, Y. et al. Immune cell PD-L1 colocalizes with macrophages and is associated with outcome in PD-1 pathway blockade therapy. Clin. Cancer Res. 26, 970–977 (2020).

    Article  CAS  PubMed  Google Scholar 

  207. Zugazagoitia, J. et al. Biomarkers associated with beneficial PD-1 checkpoint blockade in non-small cell lung cancer (NSCLC) identified using high-plex digital spatial profiling. Clin. Cancer Res. 26, 4360–4368 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Gupta, S., Zugazagoitia, J., Martinez-Morilla, S., Fuhrman, K. & Rimm, D. L. Digital quantitative assessment of PD-L1 using digital spatial profiling. Lab. Invest. 100, 1311–1317 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Sun, R. et al. A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study. Lancet Oncol. 19, 1180–1191 (2018).

    Article  CAS  PubMed  Google Scholar 

  210. Yoon, H. J. et al. Deciphering the tumor microenvironment through radiomics in non-small cell lung cancer: correlation with immune profiles. PLoS ONE 15, e0231227 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. 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 

  212. Hakozaki, T. et al. The gut microbiome associates with immune checkpoint inhibition outcomes in patients with advanced non-small cell lung cancer. Cancer Immunol. Res. 8, 1243–1250 (2020).

    Article  CAS  PubMed  Google Scholar 

  213. 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 (2020).

    Article  Google Scholar 

  214. 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 

  215. Yu, X. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat. Immunol. 10, 48–57 (2009).

    Article  CAS  PubMed  Google Scholar 

  216. Paz-Ares, L. et al. Bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial. J. Thorac. Oncol. 15, 1210–1222 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Creelan, B. et al. Abstract CT056: durable complete responses to adoptive cell transfer using tumor infiltrating lymphocytes (TIL) in non-small cell lung cancer (NSCLC): a phase I trial. Cancer Res. 80, CT056 (2020).

    Google Scholar 

  218. Du, W., Huang, H., Sorrelle, N. & Brekken, R. A. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight 3, e124184 (2018).

    Article  PubMed Central  Google Scholar 

  219. Kato, Y. et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS ONE 14, e0212513 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Wang, Z. et al. Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models. Sci. Rep. 9, 1853 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Sen, T. et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 9, 646–661 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Zheng, H. et al. HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin. Cancer Res. 22, 4119–4132 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Orillion, A. et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin. Cancer Res. 23, 5187–5201 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Reck, M. et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J. Clin. Oncol. 37, 537–546 (2019).

    Article  CAS  PubMed  Google Scholar 

  225. 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 

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Authors and Affiliations

  1. Department of Medicine (Medical Oncology), Yale School of Medicine, Yale Cancer Center, New Haven, CT, USA

    Michael J. Grant, Roy S. Herbst & Sarah B. Goldberg

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  1. Michael J. Grant
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  2. Roy S. Herbst
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All authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Correspondence to Sarah B. Goldberg.

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Competing interests

S.B.G. has acted as a consultant of AstraZeneca, Boehringer Ingelheim, Bristol–Myers Squibb, Blueprint Medicine, Daiichi–Sankyo, Genentech, Janssen, Regeneron, Sanofi-Genzyme and Takeda, and has received research funding from AstraZeneca and Boehringer Ingelheim. R.S.H. has acted as a consultant of Abbvie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals, Biodesix, Bolt Biotherapeutics, Bristol–Myers Squibb, Cybrexa Therapeutics, DynamiCure Biotechnology, eFFECTOR Therapeutics Inc., Eli Lilly and Company, EMD Serono, Foundation Medicine, Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Johnson and Johnson, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Oncternal Therapeutics, Pfizer, Refactor Health, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals Inc., Symphogen, Takeda, Tesaro, Tocagen, Ventana Medical Systems and WindMIL Therapeutics, has served on the advisory boards of AstraZeneca, Bolt Biotherapeutics, Candel Therapeutics, Checkpoint Therapeutics, Cybrexa Therapeutics, EMD Serono, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Neon Therapeutics, Novartis, Ocean Biomedical, Ribbon Therapeutics, STCube Pharmaceuticals Inc, and Xencor, and has received research funding from AstraZeneca, Eli Lilly and Company, Genentech/Roche, and Merck and Company, is a Board Member (non-executive/independent) for Immunocore Holdings Limited and Junshi Pharmaceuticals, and is a member of the Board of Directors for the International Association for the Study of Lung Cancer and the American Association for Cancer Research. M.J.G. declares no competing interests.

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Nature Reviews Clinical Oncology thanks M. Garassino, T. Mok and M. Reck for their contribution to the peer review of this work.

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Grant, M.J., Herbst, R.S. & Goldberg, S.B. Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC. Nat Rev Clin Oncol 18, 625–644 (2021). https://doi.org/10.1038/s41571-021-00520-1

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