Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC

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. Immune-checkpoint inhibitors (ICIs) are now standard-of-care therapies for patients with advanced-stage non-small-cell lung cancer (NSCLC) without a targetable driver alteration. Various ICIs or combination regimens have been approved in this setting, relative to chemotherapy, although no prospective data are available comparing the various ICI-based approaches. Here, the authors provide guidance on selecting the optimal ICI-based therapy and highlight several future research directions that will probably further improve the outcomes of patients with advanced-stage NSCLC. Key points For patients with advanced-stage NSCLC lacking a targetable driver alteration, anti-PD-1/PD-L1 antibodies are now the cornerstone of first-line therapy. Anti-PD-1/PD-L1 antibody-containing regimens can be broadly classified as immunotherapy-exclusive or chemotherapy–immunotherapy combinations, although all therapies or regimens have received approval based on their superiority to platinum-doublet chemotherapy; head-to-head comparisons of efficacy are currently lacking. Tumour cell PD-L1 expression remains the most robust clinical predictor of response to anti-PD-1/PD-L1 an