The added value of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibition as first-line treatment in non-oncogene addicted metastatic non-small cell lung cancer (NSCLC) is supported by substantive scientific evidence and clinical experience. In the absence of a true contra-indication, the use of immune checkpoint inhibitors (ICIs) is recommended as first-line therapy in phase IV NSCLC patients without targetable oncogenic driver. However, a growing challenge in clinical practice consists of the choice for one of the available first-line anti-PD-(L)1-based treatment options. The main decision in this respect consists of the choice whether to use single agent anti-PD-(L)1 therapy, or go for one of the available combination strategies.