OBJECTIVES: To estimate the relative efficacy and safety of tislelizumab with or without chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) in first-line (1L) squamous, 1L non-squamous with programmed death-ligand 1 (PD-L1) ≥ 50 %, and second- and subsequent lines (2L + ) settings via indirect treatment comparisons, following a systematic literature review (SLR) of studies investigating existing anti-programmed cell death protein-(ligand)1 (PD-[L]1) therapies. METHODS: The SLR was originally conducted in 2022 and updated in 2023. A feasibility assessment (FA) was undertaken to assess the assumptions required for network meta-analysis (NMA) among therapies approved in the UK and European Union aligning with tislelizumab's license. Outcomes included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events (TRAEs). Analyses were conducted in the hazard ratio scale for OS and PFS and in the odds ratio scale for TRAEs. Uncertainty was expressed in 95 % credible intervals. RESULTS: The SLR identified 277 total studies in 1L and 176 in 2L + NSCLC, with 23 and eight carried forward to their respective FAs. After the FA stage, 20 and eight studies qualified for the 1L and 2L + NMAs, respectively. Tislelizumab with or without chemotherapy was statistically significantly more favorable than most comparator treatments and ranked as best or second-best treatment overall for the following: PFS in 1L squamous NSCLC, OS/PFS in 1L non-squamous NSCLC with PD-L1 ≥ 50 %, and OS/PFS/TRAEs in 2L + NSCLC of any histology. For the remaining analyses (i.e. OS/TRAEs in 1L squamous NSCLC), tislelizumab with or without chemotherapy was comparable to other anti-PD-(L)1 therapies and combination therapies. CONCLUSIONS: Tislelizumab with or without chemotherapy appears to be comparable to or more favorable than other regimens of anti-PD-(L)1 therapies or combination therapies in OS/PFS/TRAEs across patients with 1L squamous NSCLC, 1L non-squamous NSCLC with PD-L1 ≥ 50 %, and 2L + NSCLC of any histology.