Tiragolumab Plus Atezolizumab Versus Placebo Plus Atezolizumab in Patients with Previously Untreated PD-L1-High, Locally Advanced Unresectable or Metastatic NSCLC (SKYSCRAPER-01): A Phase 3, Randomised, Double-Blind, Placebo-Controlled Study

Background: Tiragolumab plus atezolizumab has shown encouraging survival outcomes in metastatic non-small cell lung cancer (NSCLC), primarily in patients with programmed death-ligand 1 (PD-L1)-high tumours. We further evaluated the combination of tiragolumab plus atezolizumab in SKYSCRAPER-01.

Methods: SKYSCRAPER-01 (NCT04294810) was a randomised, double-blind, placebo-controlled, phase 3 study. Patients with previously untreated, locally advanced unresectable/metastatic PD-L1-high (by central laboratory testing) NSCLC were randomised 1:1, using a permuted block method, to receive either tiragolumab (600 mg) plus atezolizumab (1200 mg) or placebo plus atezolizumab (1200 mg), intravenously in 21-day cycles. Primary endpoints were investigator-assessed progression-free survival (INV-PFS) and overall survival (OS).

Findings: Between Mar 4, 2020, and Aug 31, 2021, 534 patients were randomised to receive tiragolumab plus atezolizumab or placebo plus atezolizumab. The primary analysis set (PD-L1-high per 22C3 assay) comprised 521 patients (tiragolumab plus atezolizumab, n=262; placebo plus atezolizumab, n=259); 389 (74·7%) patients were male, 132 (25·3%) were female. At the primary PFS analysis (Mar 12, 2022; median follow-up 9.9 months [IQR 6·2–13·8]), median INV-PFS was 7.0 months (95% CI 5·6–9·8) with tiragolumab plus atezolizumab and 5·6 months (95% CI 4·4–7·0) with placebo plus atezolizumab (HR 0·78; 95% CI 0·63–0·97; p=0·02 [non-significant]). At the final OS analysis (Sept 24, 2024; median follow-up 17·9 months [IQR 6·7–39·0]), median OS was 23·1 months (95% CI 17·7–28·8) with tiragolumab plus atezolizumab and 16.9 months (95% CI 14·6–21·3) with placebo plus atezolizumab (HR 0·87; 95% CI 0·7–1·1; p=0·22 [non-significant]). Overall, 41·2% (n=110/267) and 33·8% (n=89/263) of patients experienced grade 3–4 adverse events with tiragolumab plus atezolizumab and placebo plus atezolizumab, respectively. Four and two treatment-related deaths occurred in each group, respectively.

Interpretation: Tiragolumab plus atezolizumab did not demonstrate a statistically significant INV-PFS or OS benefit over atezolizumab in patients with previously untreated PD-L1-high NSCLC.

Declaration of Interest: SP reports institutional grants or contracts from Amgen, Arcus, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Eli Lily, GSK, iTeos, MSD, Mirati, PharmaMar, Pfizer, Promontory Therapeutics, Roche/Genentech, and Seattle Genetics; Institutional consulting fees from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BioNTech, BerGenBio, Bicycle Therapeutics, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F- Star, Foundation Medicine, Genmab, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Qlucore, MSD, Merck, Merrimack, Mirati, Nuvation Bio, Nykode Therapeutics, Novartis, Novocure, PharmaMar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Zymeworks; institutional payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events for AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, MSD, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda; support for attending meetings and/or travel to institution from AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Roche/Genentech, and Takeda; institutional fees for participation on a data safety monitoring board or advisory board for AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BioNTech, BerGenBio, Bicycle Therapeutics, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genmab, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Qlucore, MSD, Merck, Merrimack, Mirati, Nuvation Bio, Nykode Therapeutics, Novartis, Novocure, PharmaMar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Zymeworks; a leadership or fiduciary role as a board of director for Galenica. RH reports grants or contracts from AstraZeneca, Eli Lilly, Genentech, Merck, and Roche; consulting fees from AstraZeneca, Amgen, ArriVent, BMS, Candel Therapeutics, CatalYm, Checkpoint Therapeutics, Cybrexa Therapeutics, Eli Lilly, Serono, Genentech, Gilead, I-Mab Biopharma, Immunocore, Janssen, Mediflix, Merck, NextCure, Novartis, Pfizer, Regeneron, Roche, and Sanofi; support for attending meetings and/or travel from AstraZeneca, Genentech, Merck, and Roche; participation on a data safety monitoring board or advisory board from AstraZeneca, Candel Therapeutics, Checkpoint Therapeutics, Cybrexa Therapeutics, I-Mab Biopharma, Immune-Onc Therapeutics, Immunocore, Novartis; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from American Association for Cancer Research, International Association for the Study of Lung Cancer, Society for Immunotherapy of Cancer, Southwest Oncology Group of Friends of Cancer Research; stock or stock options from Bolt Biotherapeutics. Checkpoint Therapeutics, Immunocore; other financial or non-financial interests as a board member (non- executive/independent) of Immunocore and Junshi Pharmaceuticals. HH reports institutional payment from AstraZeneca, Chugai Pharm, MSD, BMS, Daiichi Sankyo, and AbbVie; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Eli Lilly, AstraZeneca, Chugai Pharm, MSD, BMS, and ONO Pharmaceutical. LPA reports grants or contracts from MSD, AstraZeneca, Pfizer, and BMS; consulting fees from Eli Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, and Daiichi Sankyo; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or editorial support from AstraZeneca, Janssen, Merck, and Mirati. 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