Background: PD-(L)1 immunotherapy plus platinum-doublet chemotherapy has been the standard 1L treatment for EGFR/ALK wild-type advanced NSCLC pts. However, pts with PD-L1 negative achieve minimal benefit from the PD-(L)1 immunotherapy plus CT. PD-(L)1 plus CTLA-4 blockade with CT in 1L treatment of PD-L1 negative NSCLC derived an improved median overall survival (OS) versus CT alone in CheckMate-9LA study (Luis Paz-Ares et al., Lancet Oncol 2021) and POSEIDON study (M L. Johnson et al., JCO 2022). QL1706 is a novel bifunctional antibody, containing a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies produced in a fixed ratio (2:1) from the same single cell and manufactured together as one product (MabPair). QL1706 monotherapy or plus CT showed impressive safety and efficacy in advanced NSCLC both in phase I and phase II studies (data have been submitted for publication). Of note, QL1706+CT exhibited promising antitumor activity in advanced PD-L1 negative NSCLC. The phase III study aims to compare the efficacy of QL1706+CT versus anti-PD-1 (tislelizumab) + CT (approved in China for 1L treatment of mNSCLC) as 1L treatment in advanced PD-L1 negative NSCLC. Methods: The phase III, multicenter, double-blinded, randomized, active-controlled study is enrolling pts aged 18-75 years with ECOG PS of 0-1, previously untreated, PD-L1 negative (TPS < 1%), EGFR/ALK wild-type, and pathologically identified stage IIIB-IV NSCLC. Eligible pts will be randomized (1:1) to receive 4-cycle treatment of QL1706 (5 mg/kg, Q3W) plus CT or tislelizumab (200 mg, Q3W) plus CT followed with maintenance treatment of QL1706 or tislelizumab monotherapy (squamous), or in combination with pemetrexed (non-squamous), until disease progression, intolerable toxicity, or for up to 2 years of immunotherapy. Stratification factors include histology (squamous vs non-squamous), brain metastasis (yes vs no), and sex (male vs female). Co-primary endpoints are progression-free survival (PFS) and OS. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DOR) assessed by investigator per RECIST v1.1, 6 mo- and 12 mo-PFS, 6 mo- and 12 mo-OS, and safety. Exploratory endpoints include PK characteristics, immunogenicity, PFS2 (defined as time from randomization to progression after first subsequent therapy or any-cause death), and efficacy (iPFS, iORR, iDCR, iDOR) by investigator per iRECIST, biomarker analysis of tumor mutation burden. The study planned to enroll 650 pts to obtain approximately 493 PFS events (HR = 0.69; Power = 94%) and 445 OS events (HR = 0.75; Power = 83%) across the QL1706+CT and tislelizumab+CT arms for the final analyses of PFS and OS, respectively. The alpha was split between PFS (α = 0.005) and OS (α = 0.02). Enrollment began from Feb 2023. Clinical trial information: NCT05690945.