ObjectiveThe monoclonal antibodies anti-programmed death protein-1 (anti–PD-1) nivolumab and pembrolizumab are the first immune checkpoint inhibitors (ICIs) approved for treatment of recurrent/metastatic head and neck carcinoma R/M HNSCC in first line and in platinum refractory disease. This network meta-analysis aims to investigate the efficacy of anti–PD-1- vs anti–PD-L1-based therapy in R/M HNSCC cancer patients through a systematic review of the literature to provide support for evidence-based treatment decisions. In particular, the effectiveness of ICIs for R/M HNSCC is analyzed according to the different mechanisms of action of the check-points inhibitory drugs in different subgroups of patients.MethodsWe did a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) in PubMed, ClinicalTrials.gov, Embase, Medline, the Cochrane Central Register of Controlled Trials, Web of Science. Our search identified a total of five randomized controlled trials: Keynote 040, Keynote 048, Eagle, Condor, Checkmate 141. These trials included 3001 patients. Treatment was sub-categorized into PD-L1–based, PD-1–based, and standard chemotherapy. Treatments were indirectly compared with anti–PD-L1-based therapy.ResultsThe network meta-analysis demonstrated no significant differences in OS between different subgroups except for the metastatic patients in which anti–PD-1-based therapy was associated with significantly less risk of death. Furthermore, anti–PD-1-based therapy appeared to be effective in smoker patients and in human papilloma–negative (HPV) patients. Conversely, anti–PD-L1-based therapy seems to be better efficient in female patients, in locally recurrent setting and in HPV positive patients.ConclusionThis is the first NMA study that aimed to indirectly compare anti–PD-1- and anti–PD-L1-based therapy in HNSCC patients. The results of our NMA could help define a profile of patient responder or resistant to specific classes of immune drugs and can be used to guide/design future studies in the novel scenario of precision immune-oncology.