Background: Based on the findings of the phase 3 PACIFIC trial, durvalumab as consolidation therapy is the standard of care for patients with unresectable Stage III NSCLC and no disease progression following chemoradiotherapy (CRT; the PACIFIC regimen). However, further improvements in outcomes are needed for this population and, to build upon the backbone of PD-L1 inhibition with durvalumab, immunotherapy combinations including anti-TIGIT, anti-CD73, and anti-NKG2a monoclonal antibodies (mAbs) are now being explored. Two potential candidates, oleclumab and monalizumab, have demonstrated encouraging clinical activity in a randomized, phase 2 trial when combined with durvalumab in this setting. Oleclumab (MEDI9447) is a human IgG1λ mAb that inhibits the function of CD73, to reduce extracellular adenosine production and thus promote antitumor immunity. Monalizumab (IPH2201) is a first-in-class, humanized, IgG4 mAb that prevents NKG2A from binding to HLA-E, which reduces inhibition of natural killer and CD8+ T cells. The combination of each of these molecules with durvalumab consolidation therapy was evaluated in the phase 2 COAST study (NCT03822351). In COAST (n = 189), patients receiving combination therapy reported numerically higher objective response rates (durvalumab plus oleclumab: 30.0%; durvalumab plus monalizumab: 35.5%; durvalumab monotherapy: 17.9%) and prolonged progression-free survival versus durvalumab alone, with no new/significant safety signals (Herbst, et al. 2022). Thus, the combination of oleclumab or monalizumab with consolidative durvalumab warrants further evaluation in a phase 3 trial. Methods: PACIFIC-9 (NCT05221840) is a phase 3, double-blind, placebo-controlled, randomized, international trial. Eligible patients (age ≥18 years) must have EGFR/ALK wild-type unresectable Stage III NSCLC, a WHO performance status of 0/1, documented PD-L1 status, and must not have progressed following ≥2 cycles of definitive, platinum-based concurrent CRT. Approximately 999 patients will be randomized (1:1:1) to receive up to 12 months of treatment (in 28-day cycles) with durvalumab plus either oleclumab (Arm A); monalizumab (Arm B); or placebo (Arm C). The primary endpoint is progression-free survival (RECIST v1.1) by blinded independent central review (BICR). Overall survival is a key secondary endpoint. Other secondary endpoints include objective response rate and duration of response (RECIST v1.1; BICR), patient-reported outcomes, PD-L1 expression on tumor cells relative to efficacy outcomes, and safety/tolerability (CTCAE v5.0). Trial enrollment is ongoing. Previously presented at the World Conference on Lung Cancer (WCLC) 2022, FPN (Final Publication Number): P1.10-01, Fabrice Barlesi et al.Clinical trial information: NCT05221840.