, 2025-05-05 10:51:00
A trial testing the combination of the anti-TIGIT antibody tiragolumab and atezolizumab vs atezolizumab in previously untreated programmed cell death ligand 1 (PD-L1)–high locally advanced unresectable or metastatic non–small cell lung cancer (NSCLC) failed to meet its primary endpoints.
Although the SKYSCRAPER-01 trial did not meet its primary endpoints, numerical advantages observed with the tiragolumab/atezolizumab combination suggest that TIGIT remains a potentially valid target in NSCLC, said Solange Peters, MD, PhD, during her presentation of the new results at the American Association for Cancer Research (AACR) Annual Meeting 2025.
“More data are needed to identify the patient population who potentially could benefit from combining an anti–PD-L1 strategy with the inhibition of the TIGIT pathway,” she said during her talk.
Peters, of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, described the importance of checkpoint inhibitors in the management of advanced NSCLC without actionable genomic alterations, particularly in patients with high PD-L1 expression. However, she noted that most patients, “probably more than 85%,” eventually experience disease progression. According to Peters, this high rate of progression despite treatment indicates an unmet need for new treatment options for this patient population.
Peters explained that TIGIT, a T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine–based activation motifs domains, has emerged as a promising immune checkpoint target. TIGIT binds to poliovirus receptor (PVR), also called CD155, on cancer cells and antigen-presenting cells, inhibiting the immune activity of T cells and natural killer cells.
“In lung cancer cells, tumor-infiltrating lymphocytes, particularly exhausted CD8+ T cells, may express high levels of TIGIT and PD-1,” Peters noted during her presentation. “Therefore, a human anti-TIGIT monoclonal antibody that blocks TIGIT binding to PVR could restore the interaction between CD226 and PVR, allowing activation of T cells and NK cells.”
Study Design
SKYSCRAPER-01 was a phase 3, double-blind, placebo-controlled, randomized trial that recruited patients between March 2020 and August 2021 at 122 sites across 20 countries. The study enrolled patients with previously untreated, locally advanced, unresectable, or metastatic NSCLC with high PD-L1 expression, good performance status (ECOG 0-1), and without EGFR/ALK alterations.
Patients were randomized 1:1 to receive either tiragolumab 600 mg intravenously (IV) plus atezolizumab 1200 mg IV or placebo plus atezolizumab 1200 mg IV every 3 weeks until disease progression or loss of clinical benefit. The final analysis included 534 randomized patients.
The primary endpoint was investigator-assessed progression-free survival (PFS) and overall survival (OS) in the primary analysis set, which included patients with PD-L1 tumor proportion score ≥ 50%, as determined with the 22C3 assay.
Secondary endpoints included investigator-assessed objective response rate (ORR) and investigator-assessed duration of response (DOR) in the primary analysis set, as well as OS in the secondary analysis set (patients with PD-L1 tumor cell ≥ 50%, as determined using the SP263 assay).
No Significant Benefit With Tiragolumab Plus Atezolizumab
At the data cutoff in March 2022, the median investigator-assessed PFS was 7.0 months with tiragolumab plus atezolizumab vs 5.6 months with placebo plus atezolizumab (hazard ratio [HR], 0.78; 95% CI = 0.63-0.97; P = .02). Although there was a slight numerical difference in the median PFS between the groups, this difference did not meet the prespecified significance threshold of P < .01.
At the final OS analysis (data cutoff September 2024), the median OS was 23.1 months with tiragolumab plus atezolizumab vs 16.9 months with placebo plus atezolizumab (HR, 0.87; 95% CI = 0.71-1.08; P = .22). Patients in the tiragolumab plus atezolizumab arm showed a higher ORR (45.8% vs 35.1%) and longer median DOR (18.0 months vs 14.6 months).
Peters said that although the primary endpoints of investigator-assessed PFS and OS were not met, “numerical improvements in both PFS and OS with tiragolumab plus atezolizumab versus placebo plus atezolizumab suggest potential antitumor activity of combination PD-L1/TIGIT targeting in NSCLC.”
Safety Profile
Safety analysis revealed increased toxicity with combination therapy. The median treatment duration was 7.5 months in the experimental arm vs 5.5 months in the control arm. The rates of any-grade toxicity, adverse events related to any treatment, adverse events leading to treatment withdrawal, and immune-related adverse events were all higher in the experimental arm than in the control arm.
The most frequent adverse events in the tiragolumab plus atezolizumab arm were pruritus, rash, decreased appetite, cough, and anemia. Immune-mediated adverse events observed in more than 5% of patients included rash, hepatitis, hypothyroidism, infusion-related reactions, hyperthyroidism, adrenal insufficiency, and pneumonitis.
Expert Perspective: What Went Wrong?
In his discussion session, Ramaswamy Govindan, MD, of Washington University School of Medicine, St. Louis, provided context for the SKYSCRAPER-01 results, which he described as “disappointing.”
Govindan compared SKYSCRAPER-01 with the earlier phase 2 CITYSCAPE study, which yielded positive results and provided the rationale for the phase 3 trial.
“If you look at the combination arm, the response rates in SKYSCRAPER-01 are a little lower, the PFS is half of what was seen in the CITYSCAPE study, and OS is much less impressive,” he said. On the contrary, the atezolizumab arm in the two trials was “roughly the same.”
Govindan pointed out several differences between the populations in the two studies, including a higher proportion of participants with liver and brain metastases and a greater proportion of men in the SKYSCRAPER-01 study. He also highlighted the sample size issue, noting, “Although the CITYSCAPE results were promising, findings were based on a small number of patients.” He further explained that the study had a population of 67, and only about half had PD-L1 ≥ 50%.
Govindan stated that variations in cohort sizes and characteristics, as well as differences in tumor biology and the tumor microenvironment, also could have contributed to the discrepancies in the findings of the two studies.
Future Directions for TIGIT Inhibitors
Despite these setbacks, both Peters and Govindan emphasized that the TIGIT pathway remains an interesting target, with other TIGIT inhibitors still under development, including domvanalimab, rilvegostomig, and belrestotug.
Govindan also said that not all TIGIT inhibitors are the same and that there is a controversy in the TIGIT field about “whether we should keep” the fragment crystallizable region of the monoclonal antibody (Fc) “active,” meaning able to engage Fc receptors and potentially trigger antibody-dependent cellular cytotoxicity, or “inactive,” meaning engineered to minimize Fc receptor engagement.
Govindan also discussed the importance of biomarker development, noting, “We should look at biomarkers before we say that TIGIT-targeted therapies do not work.”
He explained that in the CITYSCAPE study, an agnostic approach was used, and transcriptomic studies showed tumor-associated macrophages, Tregs, and monocytes as potential biomarkers of response. He added that “tumors that were enriched in macrophages, monocytes, and Tregs did well with the TIGIT combination,” suggesting that these could serve as markers for better patient selection.
Peters reported financial relationships with Lausanne University/Centre Hospitalier Universitaire Vaudois (employment), AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BioNTech, BerGenBio, Bicycle Therapeutics, Biocartis, Biolnvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly and Company, F-Star, Foundation Medicine, Genmab, Genzyme, Gilead Sciences, GSK, HUTCHMED, Illumina, Incyte, Ipsen, iTeos Therapeutics, Janssen, Qlucore, Merck Sharp & Dohme, Merck Serono, Merrimack, Mirati, Nuvation Bio, Nykode Therapeutics, Novartis, Novocure, PharmaMar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Zymeworks. Govindan reported financial relationships with Washington University School of Medicine (employment) and Amgen, Verastem, MOMA Therapeutics, and Prelude Therapeutics.
Christos Evangelou, PhD, is a freelance medical writer and science communications consultant.
