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

[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.