Immunotherapeutic approaches for small-cell lung cancer


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.

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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.


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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.

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

Correspondence to Leora Horn.

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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.

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Iams, W.T., Porter, J. & Horn, L. Immunotherapeutic approaches for small-cell lung cancer. Nat Rev Clin Oncol (2020).

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