A Phase 2 Study of Stereotactic Ablative Radiotherapy Plus Atezolizumab Plus Tiragolumab in Treatment-naïve Patients with Advanced Non-small Cell Lung Cancer

Abstract Purpose: SKYROCKET is a single-center, single-arm phase II study that evaluated the addition of SBRT to atezolizumab plus tiragolumab enhances anti-tumor efficacy in PD-L1–positive NSCLC. Patients and Methods: Patients received SBRT to all metastatic sites, and subsequently received atezolizumab and tiragolumab every 3 weeks on day 1 of each 21-day cycle with 7 days of completion of SBRT. The primary endpoint was investigator-assessed progression-free survival (PFS) from the start of SBRT. Exploratory endpoints included 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 6 months). Results: A total of 41 patients were enrolled. At a median duration of follow-up of 9.8 months, median PFS at the start of SBRT was 9.3 months (95% CI, 6.0–NR). No new safety signal was observed. ScRNA-seq of paired BL and OT (n=3) and single-time point (n=2) revealed that CD8 progenitor-exhausted (TPEX) cells markedly expanded after treatment, with high TIGIT and PD-1 expression in CD8 TPEX/TEX subsets. CD4 Tregs were reduced in the CB group but increased in the NCB group. The CB group showed reduced Treg suppression and NECTIN–TIGIT signaling, whereas NCB maintained proliferative CTLA4high/TIGIT high Tregs supported by ICAM/Galectin–CTLA4 pathways. Conclusions: SBRT followed by atezolizumab plus tiragolumab showed encouraging clinical activity with manageable safety in PD-L1–positive metastatic NSCLC.