This study provides key negative results for immune combination strategies in PD-L1–high non–small cell lung cancer, suggesting a need to re-evaluate the applicable populations and biomarker selection for TIGIT-targeted therapy. It offers important guidance for the design of future clinical trials.
Literature Overview
The article titled 'SKYSCRAPER-01: Tiragolumab in Combination With Atezolizumab in Previously Untreated PD-L1–High, Locally Advanced, Unresectable or Metastatic Non–Small Cell Lung Cancer,' published in the 'Journal of Clinical Oncology,' systematically investigates the efficacy and safety of the anti-TIGIT antibody tiragolumab in combination with the anti-PD-L1 antibody atezolizumab in patients with previously untreated, advanced non–small cell lung cancer (NSCLC) with high PD-L1 expression. Based on the promising signals from the phase II CITYSCAPE trial, this phase III study aimed to confirm survival benefits with dual immune checkpoint blockade, but ultimately failed to meet its primary endpoints, prompting important reflections on the current immunotherapy landscape.Background Knowledge
1. NSCLC accounts for over 85% of all lung cancer cases, with most patients presenting with locally advanced or metastatic disease at diagnosis, leading to poor prognosis. Although PD-1/PD-L1 inhibitors, either as monotherapy or in combination with chemotherapy, have become standard first-line treatments, a significant proportion of patients exhibit primary or acquired resistance, highlighting the urgent need for novel therapeutic strategies. 2. TIGIT, an emerging immune checkpoint molecule, is highly expressed on exhausted CD8+ T cells and regulatory T cells (Tregs) within the tumor microenvironment. By inhibiting the CD226 signaling pathway, TIGIT negatively regulates T-cell activity, making it an attractive target for combination therapy. However, multiple phase III trials (e.g., SKYSCRAPER-01, GALAXIES Lung-201) have failed to demonstrate survival benefits with TIGIT inhibitors combined with PD-1/PD-L1 antibodies, revealing bottlenecks in target selection, patient stratification, and biomarker prediction. 3. This study specifically aimed to validate the synergistic effect of dual TIGIT and PD-L1 blockade in patients with high PD-L1 expression, attempting to overcome the efficacy plateau of single-agent immunotherapy. The results suggest that more precise biomarkers (e.g., TIGIT expression levels, T-cell clonality) may be required to identify patients most likely to benefit.
Research Methods and Experiments
The study employed a multicenter, randomized, double-blind, placebo-controlled phase III design, enrolling 534 treatment-naïve NSCLC patients with high PD-L1 expression (TPS ≥50%), who were randomized 1:1 to receive either tiragolumab plus atezolizumab or placebo plus atezolizumab. The primary endpoints were investigator-assessed progression-free survival (INV-PFS) and overall survival (OS), analyzed in the primary analysis set (PAS) defined by central laboratory-confirmed PD-L1 status using the IHC 22C3 pharmDx assay. Treatment continued until disease progression or unacceptable toxicity. This design ensured robust efficacy evaluation with minimized bias, and since all patients received atezolizumab as background therapy, the incremental benefit of tiragolumab could be directly assessed.Key Conclusions and Perspectives
Research Significance and Prospects
The results of this study carry important implications for drug development: even promising signals from phase II trials may not be replicated in phase III, emphasizing the need for more reliable predictive models and translational research support. For clinical practice, in the absence of validated biomarkers, routine use of TIGIT-based combination regimens is not recommended. In terms of disease modeling, more clinically relevant animal models (e.g., humanized mouse models) that better recapitulate human immune microenvironments are needed to assess the true potential of combination immunotherapies.
Conclusion
The SKYSCRAPER-01 study failed to demonstrate that tiragolumab combined with atezolizumab is superior to atezolizumab alone in patients with PD-L1–high NSCLC, despite a numerical trend toward survival benefit. This negative outcome highlights the current limitations of TIGIT-targeted therapy in unselected populations and suggests that future efforts should focus on biomarker-driven strategies. From a translational perspective, the study underscores the necessity of mechanistic research and refined prognostic models to optimize patient selection before advancing combination immunotherapies. For the NSCLC care ecosystem, it serves as a reminder that immune combinations should not be expanded indiscriminately, but rather grounded in solid biological rationale and early translational data. Nevertheless, exploration of the TIGIT pathway remains valuable—for instance, through bispecific antibodies (e.g., rilvegostomig) or combinations with chemotherapy or other immunomodulators—which may yet redefine its clinical relevance. This study provides a critical reference for future trial designs and stands as an indispensable cornerstone in advancing precision immunotherapy.
