Integrated single-cell analysis identifies biomarkers associated with clinical benefit in patients with PD-L1 positive, advanced NSCLC treated with SBRT followed by atezolizumab plus tiragolumab
Presenter: Jii Bum (Joy) Lee, MD;PhD Session: Combination Immunotherapies Time: 4/20/2026 2:00:00 PM → 4/20/2026 5:00:00 PM
Authors
Jii Bum Lee 1 , Dong Kwon Kim 2 , Sang Hoon Lee 2 , Kyung Hwan Kim 1 , Su-Jin Choi 2 , Min Hee Hong 1 , Byoung Chul Cho 1 , Sun Min Lim 1 1 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of, 2 Yonsei University College of Medicine, Seoul, Korea, Republic of
Abstract
Background: Prior studies have shown that the addition of SBRT to immunotherapy in oligometastatic non-small cell lung cancer (NSCLC) may improve clinical outcomes. SKYROCKET is a single-center, single-arm phase II study that evaluated whether SBRT combined with atezolizumab plus tiragolumab enhances anti-tumor efficacy in PD-L1-positive oligometastatic NSCLC. Methods: Patients initially received SBRT to all oligometastatic sites, and subsequently received a fixed dose of 1200 mg IV of atezolizumab and 600 mg of tiragolumab every 3 weeks on day 1 of each 21-day cycle within 7 days of SBRT. The primary endpoint was investigator-assessed progression-free survival (PFS) from the start of SBRT. Secondary endpoints included PFS in PD-L1 high subset, objective response rate (ORR), overall survival (OS) and safety profile. Exploratory endpoints included characterization of immune remodeling and stromal dynamics via single-cell RNA sequencing (scRNA-seq) obtained from tumor biopsies at baseline (BL) and on-treatment (OT), and were further characterized as clinical benefit (CB, PR or SD ≥6 months) and no clinical benefit (NCB, PD or SD Results: A total of 41 patients were enrolled. At a median duration of follow-up of 9.8 months (IQR, 6.3-15.8), the median PFS at the start of SBRT was 9.3 months (95% CI, 6.0-NR). In patients with PD-L1 high ( > 50%), the median PFS was 11.4 months compared to 6.4 months in patients with PD-L1 low ( P = 0.029, HR, 0.39, 95% CI, 0.16-0.95). Of the 39 patients with measurable lesion, the ORR and DCR was 56% and 92%, respectively. No new safety adverse events were seen with the addition of SBRT to atezolizumab plus tiragolumab. ScRNA-seq of paired BL and OT (n=3) and single-time point (n=2) identified CD8 progenitor-exhausted (T PEX ) and terminally exhausted (T EX ) subsets. CD8 T PEX cells markedly expanded after treatment, with target engagement evidenced by high TIGIT and PD-1 expression in CD8 T PEX /T EX subsets. Pathway analyses showed enhanced T-cell activation and TCR signaling. CD4 Tregs were reduced in the CB group but increased in the NCB group. Pseudotime analysis showed T EM cells in CB preferentially transitioned into CXCL13⁺ helper states, while NCB skewed toward Treg differentiation. The CB group showed reduced Treg suppression and NECTIN-TIGIT signaling, whereas NCB maintained proliferative CTLA4 high /TIGIT high Tregs supported by ICAM/Galectin-CTLA4 pathways. Conclusion: In PD-L1 positive oligometastatic NSCLC, atezolizumab plus tiragolumab after completion of SBRT improves PFS with manageable safety profile. Combination therapy boosts cytotoxic/helper T-cell programs in CB, whereas persistent ICAM/Galectin-CTLA4-driven Tregs underlie resistance to treatment.
Disclosure
J. Lee, None.. D. Kim, None.. S. Lee, None.. K. Kim, None.. S. Choi, None.. M. Hong, None.. B. Cho, None.. S. Lim, None.
Cited in
Control: 1849 · Presentation Id: 9416 · Meeting 21436