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.

  • Review Article
  • Published:

Immunotherapeutic approaches for small-cell lung cancer

Nature Reviews Clinical Oncology volume 17, pages 300–312 (2020)Cite this article

Subjects

Abstract

Immune-checkpoint inhibitors (ICIs) are approved in the first-line and third-line settings for patients with extensive-stage or relapsed small-cell lung cancer (SCLC), respectively. In the first-line setting, the addition of the anti-programmed cell death 1 ligand 1 (PD-L1) antibody atezolizumab to chemotherapy improves overall survival (OS). In patients with relapsed disease, data from nonrandomized trials have revealed promising responses, although a significant improvement in OS over that obtained with conventional chemotherapy was not achieved in a randomized trial in this setting. Substantial research interest exists in identifying predictive biomarkers that could guide the use of ICIs in patients with SCLC. PD-L1 expression is typically low or absent in SCLC, which has precluded its use as a predictive biomarker. Tumour mutational burden might have some predictive value, although blood-based measures of tumour mutational burden did not have predictive value in patients receiving atezolizumab plus chemotherapy in the first-line setting. After three decades, ICIs have finally enabled an improvement in OS for patients with SCLC; however, a substantial amount of research remains to be done, including identifying the optimal therapeutic strategy and predictive biomarkers. In this Review, we describe the available data on clinical efficacy, the emerging evidence regarding biomarkers and ongoing clinical trials using ICIs and other immunotherapies in patients with SCLC.

Key points

  • Immune-checkpoint inhibitors (ICIs) are approved as first-line and third-line therapies for patients with advanced-stage small-cell lung cancer (SCLC).

  • In the first-line setting, the anti-programmed cell death 1 ligand 1 ICI atezolizumab plus chemotherapy has been shown to improve overall survival, relative to chemotherapy alone.

  • In the relapsed setting, nonrandomized data reveal promising responses to several ICIs that have not been corroborated in randomized trials.

  • No broadly accepted biomarkers that predict benefit from ICI have been identified to date.

  • Many ongoing trials are evaluating the performance of immune-based treatment strategies in patients with SCLC; these will hopefully enable the optimization of immune-based treatment strategies in this patient population.

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: Predictive biomarkers of response and/or survival in patients receiving immune-checkpoint inhibitors for small-cell lung cancer.
Fig. 2: Mechanisms of action of immunotherapies and other novel agents being tested in combination with immunotherapies in patients with small-cell lung cancer.

Similar content being viewed by others

References

  1. Bernhardt, E. B. & Jalal, S. I. Small cell lung cancer. Cancer Treat. Res. 170, 301–322 (2016).

    PubMed  Google Scholar 

  2. Gazdar, A. F. & Minna, J. D. Developing new, rational therapies for recalcitrant small cell lung cancer. J. Natl Cancer Inst. 108, djw119 (2016).

    PubMed  Google Scholar 

  3. Horn, L. et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Antonia, S. J. et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 17, 883–895 (2016).

    CAS  PubMed  Google Scholar 

  6. Schultheis, A. M. et al. PD-L1 expression in small cell neuroendocrine carcinomas. Eur. J. Cancer 51, 421–426 (2015).

    CAS  PubMed  Google Scholar 

  7. Hellmann, M. D. et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell 33, 853–861.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Boumber, Y. Tumor mutational burden (TMB) as a biomarker of response to immunotherapy in small cell lung cancer. J. Thorac. Dis. China 10, 4689–4693 (2018).

    Google Scholar 

  9. Gadgeel, S. M. et al. Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC). J. Thorac. Oncol. 13, 1393–1399 (2018).

    PubMed  PubMed Central  Google Scholar 

  10. Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Ott, P. A. et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J. Clin. Oncol. 35, 3823–3829 (2017).

    CAS  PubMed  Google Scholar 

  12. Carter, L. et al. Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer. Nat. Med. 23, 114–119 (2016).

    PubMed  Google Scholar 

  13. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nowak, A. K. et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J. Immunol. 170, 4905–4913 (2003).

    CAS  PubMed  Google Scholar 

  15. Nowak, A. K., Robinson, B. W. & Lake, R. A. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res. 62, 2353–2358 (2002).

    CAS  PubMed  Google Scholar 

  16. van der Most, R. G. et al. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol. Immunother. 58, 1219–1228 (2009).

    PubMed  Google Scholar 

  17. Bonanno, L. et al. The role of immune microenvironment in small-cell lung cancer: distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes. Eur. J. Cancer 101, 191–200 (2018).

    CAS  PubMed  Google Scholar 

  18. Wang, H. et al. Prognostic significance of PD-L1 expression and CD8+ T cell infiltration in pulmonary neuroendocrine tumors. Diagn. Pathol. 13, 30 (2018).

    PubMed  PubMed Central  Google Scholar 

  19. Berghoff, A. S. et al. Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC). J. Neurooncol. 130, 19–29 (2016).

    CAS  PubMed  Google Scholar 

  20. Iams, W. T. et al. Improved prognosis and increased tumor-infiltrating lymphocytes in patients who have SCLC with neurologic paraneoplastic syndromes. J. Thorac. Oncol. 14, 1970–1981 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ishii, H. et al. Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J. Thorac. Oncol. 10, 426–430 (2015).

    CAS  PubMed  Google Scholar 

  22. George, J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47–53 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Poirier, J. T. et al. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2. Oncogene 34, 5869–5878 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Huang, Y. H. et al. POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev. 32, 915–928 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Carney, D. N. et al. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res. 45, 2913–2923 (1985).

    CAS  PubMed  Google Scholar 

  26. Wooten, D. J. et al. Systems-level network modeling of small cell lung cancer subtypes identifies master regulators and destabilizers. Preprint at bioRxiv https://doi.org/10.1101/506402 (2018).

    Article  Google Scholar 

  27. McColl, K. et al. Reciprocal expression of INSM1 and YAP1 defines subgroups in small cell lung cancer. Oncotarget 8, 73745–73756 (2017).

    PubMed  PubMed Central  Google Scholar 

  28. Poirier, J. T. et al. Selective tropism of Seneca Valley virus for variant subtype small cell lung cancer. J. Natl Cancer Inst. 105, 1059–1065 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Borromeo, M. D. et al. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep. 16, 1259–1272 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mollaoglu, G. et al. MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to aurora kinase inhibition. Cancer Cell 31, 270–285 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rudin, C. M. et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat. Rev. Cancer 19, 289–297 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Wargo, J. A., Reuben, A., Cooper, Z. A., Oh, K. S. & Sullivan, R. J. Immune effects of chemotherapy, radiation, and targeted therapy and opportunities for combination with immunotherapy. Semin. Oncol. 42, 601–616 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Reck, M. et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J. Clin. Oncol. 34, 3740–3748 (2016).

    CAS  PubMed  Google Scholar 

  34. Reck, M. L. S. et al. IMPower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann. Oncol. 30, mdz264 (2019).

    Google Scholar 

  35. Paz-Ares, L. et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394, 1929–1939 (2019).

    CAS  PubMed  Google Scholar 

  36. Paz-Ares, L. et al. Overall survival with durvalumab plus etoposide-platinum in first-line extensive-stage SCLC: results from the CASPIAN study. J. Thorac. Oncol. 14, S7–S8 (2019).

    Google Scholar 

  37. Rossi, A. et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J.Clin. Oncol. 30, 1692–1698 (2012).

    CAS  PubMed  Google Scholar 

  38. Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 349, 1543–1554 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Owonikoko, T. K. et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): results from the double-blind, randomized phase III CheckMate 451 study (LBA1_PR). Ann. Oncol. 30, mdz094 (2019).

    Google Scholar 

  42. Ready, N. et al. Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032. J. Thorac. Oncol. 14, 237–244 (2019).

    CAS  PubMed  Google Scholar 

  43. Reck, M. V. D. et al. Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy in recurrent small cell lung cancer (SCLC): results from CheckMate 331. Ann. Oncol. 29 (suppl. 10), x39–x43 (2018).

    Google Scholar 

  44. Chung et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. J. Clin. Oncol. 36, 8506 (2018).

  45. Pujol, J. L. et al. A randomized non-comparative phase II study of anti-programmed cell death-ligand 1 atezolizumab or chemotherapy as second-line therapy in patients with small cell lung cancer: results from the IFCT-1603 trial. J. Thorac. Oncol. 14, 903–913 (2019).

    CAS  PubMed  Google Scholar 

  46. Ready, N. E. et al. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort. J. Thorac. Oncol. https://doi.org/10.1016/j.jtho.2019.10.004 (2019).

    Article  PubMed  Google Scholar 

  47. 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).

    PubMed  PubMed Central  Google Scholar 

  48. Ott, P. A. et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J. Clin. Oncol. 37, 318–327 (2019).

    PubMed  Google Scholar 

  49. Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. Danaher, P. et al. Pan-cancer adaptive immune resistance as defined by the tumor inflammation signature (TIS): results from The Cancer Genome Atlas (TCGA). J. Immunother. Cancer 6, 63 (2018).

    PubMed  PubMed Central  Google Scholar 

  51. Frampton, G. M. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat. Biotechnol. 31, 1023–1031 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gandara, D. R. et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat. Med. 24, 1441–1448 (2018).

    CAS  PubMed  Google Scholar 

  53. Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).

    PubMed  PubMed Central  Google Scholar 

  54. Garassino, M. et al. KEYNOTE 189: tumor mutation burden not significantly associated with efficacy of pembrolizumab. Presented at IASLC World Conference on Lung Cancer 2019.

  55. Langer, C. et al. KEYNOTE 021: tumor mutation burden not significantly associated with efficacy of pembrolizumab. Presented at IASLC World Conference on Lung Cancer 2019.

  56. Sadelain, M., Brentjens, R. & Riviere, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Springuel, L. et al. Chimeric antigen receptor-T cells for targeting solid tumors: current challenges and existing strategies. BioDrugs 33, 515–537 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Slaney, C. Y., Wang, P., Darcy, P. K. & Kershaw, M. H. CARs versus BiTEs: a comparison between T cell-redirection strategies for cancer treatment. Cancer Discov. 8, 924–934 (2018).

    CAS  PubMed  Google Scholar 

  59. NCCN Guidelines: Small Cell Lung Cancer Version 1 (National Comprehensive Cancer Network, 2019).

Download references

Acknowledgements

W.T.I. acknowledges support from the National Institutes of Health and National Cancer Institute Vanderbilt Clinical Oncology Research Career Development Award (VCORCDP) 2K12CA090625-17 and an American Society of Clinical Oncology/Conquer Cancer Foundation Young Investigator Award.

Author information

Authors and Affiliations

  1. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

    Wade T. Iams & Leora Horn

  2. West Cancer Care, Memphis, TN, USA

    Jason Porter

Authors
  1. Wade T. Iams
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jason Porter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leora Horn
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made a substantial contribution to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Leora Horn.

Ethics declarations

Competing interests

W.T.I. has acted as a consultant for Defined Health, Genentech and Outcomes Insights. L.H. reports clinical trial funding from BMS, Boehringer Ingelheim and Xcovery; and has acted as a consultant for AbbVie, AstraZeneca, EMD Serono, Incyte, Merck, Pfizer, Roche-Genentech, Tesaro and Xcovery. J.P. declares no competing interests.

Additional information

Publisher’s note

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iams, W.T., Porter, J. & Horn, L. Immunotherapeutic approaches for small-cell lung cancer. Nat Rev Clin Oncol 17, 300–312 (2020). https://doi.org/10.1038/s41571-019-0316-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-019-0316-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer