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Background: Targeted inhibition of the PD-L1-PD-1 pathway might be further amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE trial, we aimed to assess the preliminary efficacy and safety of tiragolumab plus atezolizumab (anti-PD-L1) therapy as first-line treatment for non-small-cell lung cancer (NSCLC)., Methods: CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako, Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with measurable disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe, Asia, and the USA. Patients were randomly assigned (1:1), via an interactive voice or web-based response system, to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3 weeks. Investigators and patients were masked to treatment assignment. The co-primary endpoints were investigator-assessed objective response rate and progression-free survival as per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population, analysed after approximately 80 progression-free survival events had been observed in the primary population. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is ongoing., Findings: Patients were enrolled between Aug 10, 2018, and March 20, 2019. At data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients assessed for eligibility were randomly assigned to receive tiragolumab plus atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary analysis, after a median follow-up of 5·9 months (4·6-7·6, in the intention-to-treat population, 21 patients (31·3% [95% CI 19·5-43·2]) in the tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7-25·7]) in the placebo plus atezolizumab group had an objective response (p=0·031). Median progression-free survival was 5·4 months (95% CI 4·2-not estimable) in the tiragolumab plus atezolizumab group versus 3·6 months (2·7-4·4) in the placebo plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37-0·90], p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%) patients receiving placebo plus atezolizumab had serious treatment-related adverse events. The most frequently reported grade 3 or worse treatment-related adverse event was lipase increase (in six [9%] patients in the tiragolumab plus atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab plus atezolizumab group., Interpretation: Tiragolumab plus atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival compared with placebo plus atezolizumab in patients with chemotherapy-naive, PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was well tolerated, with a safety profile generally similar to that of atezolizumab alone. These findings demonstrate that tiragolumab plus atezolizumab is a promising immunotherapy combination for the treatment of previously untreated, locally advanced unresectable or metastatic NSCLC., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests BCC reports research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, Merck Sharp & Dohme, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence; royalties from Champions Oncology; and consulting fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, and Blueprint Medicines; participates on a scientific advisory board for KANAPH Therapeutic, Brigebio Therapeutics, Cyrus Therapeutics, Guardant Health, and Joseah BIO; is on the Board of Directors for Interpark Bio Convergence and Gencurix; holds stock in TheraCanVac, Gencurix, Bridgebio Therapeutics, KANAPH Therapeutic, Cyrus Therapeutics, and Interpark Bio Convergence; and is the founder of DAAN Biotherapeutics. DRA reports personal payment or honoraria from Roche, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly, Pfizer, and Novartis; and institutional support for attending meetings or travel from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme and Novartis. MH reports consulting or advisory fees from IntegraConnect, Coherus Biosciences, Athenex, Karyopharm Therapeutics, Bristol-Myers Squibb, AstraZeneca, and Mirati Therapeutics. AJP is on the Executive Board of Florida Cancer Specialists. KHL reports consulting fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Lilly, Pfizer, and AstraZeneca. BM reports consulting fees from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Takeda; payment or honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, and AstraZeneca; support for attending meetings or travel from Merck Sharp & Dohme and AstraZeneca; and a leadership or fiduciary role in the Spanish Lung Cancer Group. SH is a consultant–advisor to AstraZeneca and Takeda. JCHY reports grants from AstraZeneca; personal fees from Amgen, AstraZeneca, Bayer, Boehringrer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche–Genentech, Takeda Oncology, and Yuhan Pharmaceuticals; and institutional fees for advisory or consulting services from Amgen, AstraZeneca, Bayer, Boehringrer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Roche–Genentech, Takeda Oncology, Yuhan Pharmaceuticals, and Johnson and Johnson. FB reports personal consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F Hoffmann-La Roche, Novartis, Merck, Mirati, Merck Sharp & Dohme, Pierre Fabre, Pfizer, Seattle Genetics, and Takeda; and institutional consulting fees from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F Hoffmann-La Roche, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, Merck Sharp & Dohme, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda. DHL reports personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, ChongKeunDang, Janssen, Merck, Merck Sharp & Dohme, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, AbbVie, Takeda, Genexine, Menarini, and BC Pharma; and non-financial support from Takeda and Blueprint Medicine. LPA reports grants or contracts from Merck Sharp & Dohme, AstraZeneca, Pfizer, and Bristol-Myers Squibb; consulting fees from Lilly, Bristol-Myers Squibb, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Blueprint, Bristol-Myers Squibb, and Mirati; payment or honoraria from AstraZeneca, Janssen, Merck, Mirati and Sanofi; and a leadership or fiduciary role in Genomica and Altum Sequency. RWH reports stock and stock options with F Hoffmann-La Roche, and is an employee of Genentech. NSP is an employee of Genentech. PT reports stock and stock options with F Hoffmann-La Roche. XY is an employee of Genentech. RM is an employee of Genentech and reports stock with Genentech. MLJ reports grants from AbbVie, Amgen, Apexigen, Arcus Biosciences, Array Biopharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, EMD Serono, Genentech–Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Oncology, Novartis, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals–Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, TMUNITY Therapeutics, University of Michigan, and WindMIL; and institutional fees for consulting services from AbbVie, Amgen, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, CytomX, Daiichi Sankyo, EMD Serono, Genentech–Roche, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, WindMIL, Achilles Therapeutics, Bristol-Myers Squibb, Editas Medicine, Eisai, G1 Therapeutics, Ideaya Biosciences, Lilly, and Association of Community Cancer Centers. MC, NS, and XY declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)