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.

Fig. 1 |. Predictive biomarkers of response and/or survival in patients receiving immune-checkpoint inhibitors for small-cell lung cancer.

Various tumour-based and/or blood-based assays have been evaluated for their ability to predict clinical benefit from immune-checkpoint inhibitors in patients with small-cell lung cancer. Biomarkers that are thought to continue to hold potential clinical predictive value include tumour mutational burden (TMB) and tumour-infiltrating lymphocyte RNA expression. Biomarkers that are thought to not hold predictive value based on data from larger analyses include tumour programmed cell death 1 ligand 1 (PD-L1) expression and blood-based TMB. Biomarkers that have only been evaluated in very small numbers of patients include circulating tumour cells (CTCs), combined tumour plus tumour-infiltrating immune cell PD-L1 expression, and PD-L1 expression at the tumour–stromal interface. ECM, extracellular matrix.

Fig. 2 |. Mechanisms of action of immunotherapies and other novel agents being tested in combination with immunotherapies in patients with small-cell lung cancer.

Immunotherapies and other novel agents currently being evaluated in combination with immunotherapies in patients with small-cell lung cancer include immune-checkpoint inhibitors (anti-programmed cell death protein 1 (PD-1), anti-programmed cell death 1 ligand 1 (PD-L1), anti-cytotoxic T lymphocyte protein 4 (CTL A-4), anti-L AG3 and anti-TIM3 antibodies), bispecific antibodies (such as those targeting CD3 plus DLL3 or PD-1 plus TIM3), engineered T cell therapies (such as anti-DLL3 chimeric antigen receptor (CAR) T cells), neoantigen vaccines, antiproliferative agents (AKT inhibitors) and DNA damage repair-directed therapies (poly(ADP-ribose) polymerase (PARP) inhibitors, serine/threonine-protein kinase ATR (ATR) inhibitors and Wee1-like protein kinase (WEE1) inhibitors). BiTE, bispecific T cell engager ; DC, dendritic cell; TCR , T cell receptor.