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.
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