Background: The PACIFIC trial (NCT02125461) established up to 12 months of consolidation therapy with durvalumab as standard of care (SoC) for patients with unresectable stage III non-small-cell lung cancer (NSCLC) and no disease progression after platinum-based cCRT. To improve outcomes further in this population, novel immunotherapy combinations that build on the backbone of PD-L1 inhibition with durvalumab are being explored. Domvanalimab (AB154) is a Fc-silent humanized IgG1 monoclonal antibody that blocks interaction of the T cell immunoreceptor with Ig and ITIM domains (TIGIT; upregulated by immune cells) with CD112 and CD155 (expressed by tumor and antigen-presenting cells), reducing inhibition of T cells and natural killer cells and, thereby, promoting antitumor activity. The combination of TIGIT inhibition with PD-(L)1 inhibition has shown encouraging activity in phase 1 and 2 trials in metastatic NSCLC, with enriched benefit observed among patients with PD-L1 positive tumors (Rodriguez-Abreu, et al. 2020; Niu, et al. 2020). In ARC-7 (NCT04262856), a randomized, phase 2 trial, the combination of domvanalimab and PD-1 inhibition was associated with improvement in progression-free survival (PFS) versus PD-1 inhibition alone (HR, 0.55; 95% CI, 0.31–1.0) in treatment-naïve patients with metastatic NSCLC and high PD-L1 expression (tumor proportion score ≥50%) (Johnson, et al. 2022). PACIFIC-8 (NCT05211895) is assessing the efficacy and safety of durvalumab combined with domvanalimab as consolidation therapy in patients with PD-L1 positive, unresectable stage III NSCLC and no disease progression after platinum-based cCRT. Methods: PACIFIC-8 is a phase 3, double-blind, placebo-controlled, randomized, global trial. Eligible patients (aged ≥18 years) must have PD-L1 positive, unresectable stage III NSCLC (tumor cell [TC] expression ≥1% by central lab; VENTANA SP263 IHC assay), WHO performance status 0/1, documented EGFR/ALK wild-type tumor status, and not have progressed following definitive, platinum-based cCRT (≥2 cycles). Approximately 860 patients will be randomized (1:1) to receive SoC durvalumab (1500 mg IV) combined with either domvanalimab (20 mg/kg IV) or placebo, every 4 weeks for up to 12 months. The primary endpoint is PFS (RECIST v1.1) by blinded independent central review (BICR) in patients with PD-L1 TC ≥50%. Secondary endpoints include PFS (RECIST v1.1; BICR) in patients with PD-L1 TC ≥1%, overall survival, objective response rate and duration of response (RECIST v1.1; BICR), safety/tolerability, and patient-reported outcomes. Trial enrollment is ongoing. Previously presented at the European Society for Medical Oncology (ESMO) Congress 2022, FPN (Final Publication Number): 971TiP, Mustafa Özgüroğlu et al. – Reused with permission.Clinical trial information: NCT05211895.