Abstract CT051: SKYSCRAPER-01: A phase III, randomized trial of tiragolumab (tira) + atezolizumab (atezo) versus placebo (pbo) + atezo in patients (pts) with previously-untreated PD-L1-high, locally advanced unresectable/metastatic NSCLC

Abstract Background: Tiragolumab (tira) + atezolizumab (atezo) has shown encouraging survival outcomes in pts with metastatic NSCLC, primarily in pts with PD-L1-high tumors (tumor proportion score [TPS] ≥50%). SKYSCRAPER-01 (NCT04294810) is a phase III, double-blind, placebo-controlled, randomized trial investigating the efficacy and safety of first-line tira + atezo in pts with PD-L1-high NSCLC. Methods: Eligible pts (previously untreated; PD-L1-high, locally advanced unresectable/metastatic NSCLC; EGFR/ALK wildtype) were randomized 1:1 to receive tira 600 mg IV + atezo 1200 mg IV or pbo + atezo 1200 mg IV every 3 weeks until disease progression, loss of clinical benefit, or unacceptable toxicity. Primary endpoints: investigator-assessed progression-free survival (INV-PFS) and overall survival (OS) in the primary analysis set (PAS; TPS ≥50%; 22C3 assay). Secondary endpoints: INV-objective response rate (INV-ORR) and INV-duration of response (INV-DOR) in the PAS; OS in the secondary analysis set (SAS; tumor cell [TC] ≥50%; SP263 assay). Results: A total of 534 pts were randomized (tira + atezo, n=266; pbo + atezo, n=268). Pt characteristics were balanced between treatment arms. At the final PFS analysis (data cut-off 12 Mar 2022; median follow-up 9.9 months), median INV-PFS was 7.0 months with tira + atezo and 5.6 months with pbo + atezo (HR 0.78; 95% CI 0.63, 0.97; p=0.02; PAS). At the final OS analysis (data cut-off 24 Sep 2024; median follow-up 17.9 months), median OS was 23.1 months with tira + atezo and 16.9 months with pbo + atezo (HR 0.87; 95% CI 0.71, 1.08; p=0.22; PAS; Table). Tira + atezo demonstrated an acceptable safety profile, consistent with previous observations. Table PAS (TPS ≥50% per 22C3 assay) Tira + atezo Pbo + atezo (n=262) (n=259) Median PFS, months (95% CI)*† 7.0 (5.6, 9.8) 5.6 (4.4, 7.0) HR (95% CI); p-value 0.78 (0.63, 0.97); p=0.02 Median OS, months (95% CI)*† 23.1 (17.7, 28.8) 16.9 (14.6, 23.1) HR (95% CI); p-value 0.87 (0.71, 1.08); p=0.22 ORR, %* 45.8 35.1 Median DOR, months (95% CI)* 18.0 (13.6, 24.4) 14.6 (9.7, 18.6) SAS (TC ≥50% per SP263 assay) Tira + atezo Pbo + atezo (n=211) (n=209) Median OS, months (95% CI)* 24.6 (17.9, 32.0) 20.6 (16.6, 29.3) HR (95% CI) 0.93 (0.73, 1.18) Safety evaluable set ‡ Tira + atezo Pbo + atezo (n=267) (n=263) Any grade AEs, % 95.9 91.3 Grade 3-4 AEs, % 41.2 33.8 Grade 5 AEs, % 10.9 9.9 Treatment-related grade 5 AEs, % 1.5 0.8 AEs leading to treatment withdrawal, % 16.1 6.5 Any grade AESIs, % 70.0 50.6 * PFS analysis: data cut-off 12 Mar 2022 (PFS final analysis/first OS interim analysis); OS ORR, and DOR analysis: data cut-off 24 Sep 2024 (OS final analysis). PFS, ORR and DOR were assessed by the investigator. † Primary endpoints. ‡ All randomized patients who received ≥1 dose of study treatment. AE, adverse event; atezo, atezolizumab; AESIs, adverse events of special interest; CI, confidence interval; DOR, duration of response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PAS, primary analysis set; pbo, placebo; PFS, progression-free survival; SAS, secondary analysis set; TC, tumor cell; tira, tiragolumab; TPS, tumor proportion score. Conclusion: The primary endpoints of INV-PFS and OS were not met in the SKYSCRAPER-01 study. Numerical improvements in both PFS and OS with tira + atezo versus pbo + atezo suggest potential antitumor activity of TIGIT targeting in NSCLC. Citation Format: Solange Peters, Roy Herbst, Hidehito Horinouchi, Luis Paz-Ares, Melissa Johnson, Benjamin Solomon, Mahmut Gumus, Mustafa Erman, Igor Bondarenko, Dong-Wan Kim, Enriqueta Felip, Alessandro Morabito, Maciej Bryl, Raymond Meng, Chipman Stroud, Palak Kundu, Xiaohui Wen, Namrata Patil, Meilin Huang, Byoung Chul Cho. SKYSCRAPER-01: A phase III, randomized trial of tiragolumab (tira) + atezolizumab (atezo) versus placebo (pbo) + atezo in patients (pts) with previously-untreated PD-L1-high, locally advanced unresectable/metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT051.