Immunotherapeutic approaches for small-cell lung cancer

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. Patients with small-cell lung cancer (SCLC) have historically received chemotherapy, typically with poor survival outcomes. In the past few years, the combination of immune-checkpoint inhibitors (ICIs) with chemotherapy has provided a more effective alternative to chemotherapy alone. Nonetheless, durations of survival are often short, and no robust biomarkers of response are available. In this Review, the authors provide a summary of the efficacy and safety of ICIs in patients with SCLC, and also highlight potential novel immunotherapeutic approaches that are currently in the early stages of investigation. 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.