Tiragolumab Plus Atezolizumab Fails to Meet Survival End Points in Previously-Untreated, PD-L1–High NSCLC

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Treatment with tiragolumab (MTIG7192A) plus atezolizumab (Tecentriq) did not generate a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) compared with atezolizumab alone in the first-line treatment of patients with locally advanced, unresectable or metastatic, PD-L1–high non–small cell lung cancer (NSCLC), failing to meet the primary end points of the phase 3 SKYSCRAPER-01 trial (NCT04294810).1

According to findings presented during the 2025 AACR Annual Meeting, at a median follow-up of 6.4 months, the median investigator-assessed progression-free survival (PFS) in the primary analysis set was 7.0 months (95% CI, 5.6-9.8) with tiragolumab plus atezolizumab (n = 262) vs 5.6 months (95% CI, 4.4-7.0) with atezolizumab alone (n = 259), resulting in a HR of 0.78 (95% CI, 0.63-0.97; P = .02). Despite showing numerical improvements, this result was not deemed statistically significant, as the prespecified alpha threshold for significance was set at P < 0.001. The 6-, 12-, and 18-month PFS rates with the doublet were 54.6%, 37.3%, and 24.3%, respectively. Corresponding PFS rates in the control arm were 47.8%, 24.9%, and 20.5%

Similarly, at a median follow-up of 36.8 months, the median OS was 23.1 months (95% CI 17.7-28.8) in the combination arm vs 16.9 months (95% CI, 14.6-21.3) in the control arm (HR, 0.87; 95% CI, 0.71-1.08; P= .22). The 6-, 12-, and 18-month OS rates with the doublet were 67.3%, 47.7%, and 38.3%, respectively. Corresponding OS rates in the control arm were 62.6%, 41.9%, and 33.6%.

“Numerical improvements in both investigator-assessed PFS and OS [were observed] using tiragolumab plus atezolizumab vs [atezolizumab alone] and suggest potential antitumor activity of the combination of PD-L1 and TIGIT inhibition in NSCLC,” presenting and lead study author Solange Peters, MD, PhD, stated in a presentation of the data. “Further data… are needed to identify the patient population who potentially could benefit from combining an anti-PD-1 strategy with inhibition of the TIGIT pathway.”

Peters is a full professor and chair of Medical Oncology and the Thoracic Malignancies Program in the Department of Oncology at the University Hospital of Lausanne in Switzerland.

Study Rationale and Overview

Checkpoint inhibitors are the frontline standard of care for patients with locally advanced or metastatic NSCLC without actionable genomic alterations; however, more than 85% of patients eventually experience disease progression, underscoring a significant unmet need, Peters explained.

TIGIT has emerged as a promising immune checkpoint target for this patient population, as it is highly expressed on activated T cells, natural killer (NK) cells, and regulatory T cells. By binding to PVR itself or outcompeting PVR to bind to CD226, TIGIT inhibits immune activation. In NSCLC, exhausted CD8-positive tumor-infiltrating lymphocytes often co-express TIGIT and PD-1. Tiragolumab, an anti-TIGIT monoclonal antibody, blocks TIGIT-PVR interaction to restore CD226-mediated activation of T cells and NK cells. When combined with checkpoint inhibitors, such as atezolizumab, this agent could accordingly enhance antitumor responses.

Notably, the combination of tiragolumab received FDA breakthrough designation as upfront treatment for patients with metastatic, PD-L1–high, EGFR and ALK wild-type NSCLC in January 2021.2 This regulatory decision was supported by the phase 2 CITYSCAPE trial (NCT03563716), which showed clinically meaningful improvements in overall response rate (ORR) and PFS in the intention-to-treat (ITT) population compared with placebo plus atezolizumab in patients with chemotherapy-naive, locally advanced or metastatic NSCLC.1

“What was quite obvious is that the response rate was increased in the ITT population, but this benefit was only driven by these patients having a tumor with a high PD-L1 [tumor proportion score (TPS)] of 50% or higher, and nothing was happening in the 1% to 49% [TPS group],” Peters explained, citing data from a post hoc analysis of the study. “This was also nicely translated, looking at the PFS…and mirrored for OS.”

Such findings from CITYSCAPE provided the impetus for the randomized, double-blind, SKYSCRAPER-01 trial, which enrolled patients with previously untreated, locally advanced, unresectable or metastatic NSCLC with high PD-L1 expression who did not display EGFR or ALK mutations and had an ECOG performance status (PS) of 0 or 1.

Upon enrollment, patients were stratified according to ECOG PS, histology (squamous vs nonsquamous), and geographic region (Asia vs non-Asia). Eligible patients were then randomly assigned 1:1 to receive 600 mg of intravenous (IV) tiragolumab plus 1200 mg of intravenous atezolizumab once every 3 weeks on day 1 of each 21-day cycle, or placebo plus atezolizumab until disease progression, loss of clinical benefit, or unacceptable toxicity.

The study’s co-primary end points were OS and PFS in the primary analysis set, which comprised 521 patients with high PD-L1 tumor expression per the 22C3 assay. Secondary end points included OS and PFS in the secondary analysis set, which included patients with high PD-L1 tumor expression per the SP263 assay; ORR; DOR; and safety. Notably, all patients who received 1 or more doses of any treatment were included in the safety-evaluable set.

A total of 534 patients were recruited between March 4, 2020, and August 31, 2021, from 122 sites in 22 countries. The data cutoffs for the PFS and final OS analyses were March 12, 2022, and September 24, 2024.

Baseline characteristics in the primary analysis were well balanced between treatment arms. In total, 41.6% of patients in the tiragolumab/atezolizumab arm (n = 262) and 45.6% of those in the placebo/atezolizumab arm (n = 259) were younger than 65 years of age. The majority of patients were male (76.0%; 73.4%); White (69.5%; 68.7%); from non-Asian countries (73.3%; 73.0%), had an ECOG PS of 1 (61.1%; 62.5%), and had nonsquamous disease histology (72.9%; 73.4%). Regarding smoking history, most patients were previous smokers (64.5%; 62.9%), followed by current smokers (26.7%; 26.3%) and never smokers (8.8%; 10.8%). Brain (17.2%; 16.6%) and liver (17.2%; 17.0%) metastases were also observed.

Additional Efficacy Data

At the September 2024 data cutoff, secondary analyses using the 263 PD-L1 assay showed a median PFS of 8.3 months (95% CI, 6.2-11.3) vs 5.7 months (95% CI, 4.7-7.3) in the doublet and control arms, respectively, (HR, 0.86; 95% CI, 0.69-1.06). The median OS was 24.6 months (95% CI, 17.9-32.0) vs 20.6 months (95% CI, 16.6-29.3) for the combination vs control arms, respectively, (HR, 0.93; 95% CI, 0.73-1.18).

In terms of responses, the tiragolumab plus atezolizumab arm demonstrated a numerically higher ORR of 45.8% compared with 35.1% in the control arm, along with a longer median duration of response of 18.0 months (95% CI, 13.6-24.4) vs 14.6 months (95% CI, 9.7-18.6). Best responses in the doublet arm included a complete response (CR; 1.5%), partial response (PR; 44.3%), stable disease (SD; 22.1%), and disease progression (PD; 24.4%). Corresponding CR, PR, SD, and PD rates in the control arm were 1.2%, 34.0%, 27.4%, and 26.3%.

Safety Considerations and Ongoing Investigations

Safety analysis showed a longer median treatment duration in the combination arm, at 7.5 months with tiragolumab and 7.6 months with atezolizumab vs 5.5 months for both placebo and atezolizumab. Moreover, the incidence of grade 3/4 all-cause, treatment-related (TRAEs), and immune-mediated adverse effects (AEs) was approximately 10% higher in the combination vs control arm, Peters noted.

All-cause, any-grade AEs occurred in 95.9% and 91.3% of patients in the doublet vs control arms. Grade 3/4 all-cause adverse effects (AEs) were observed in both arms (41.2% vs 33.8%), as were grade 5 AEs (10.9% vs 9.9%). Serious AEs occurred at similar rates between arms (43.1% vs 41.1%); however, AEs leading to treatment withdrawal were higher with the combination (16.1%) vs atezolizumab alone (6.5%).

Treatment-related AEs (TRAEs) were reported in 75.7% vs 60.1% of patients in the combination and control arms, respectively. Immune-mediated AEs occurred in 70.0% and 50.6% of patients in these respective groups. Notably, the incidence of grade 3/4 all-cause TRAEs and immune-mediated AEs was approximately 10% higher in the combination vs control arm (TRAEs = 19.9% vs 9.5%; immune-mediated AEs = 16.1% vs 9.9%). Grade 5 TRAEs were reported in 1.5% and 0.8% of patients in the combination and control arms, respectively; grade 5 immune-mediated AEs were reported in 0.7% and 0.8% of patients. Notably, systemic corticosteroids were required for 24.3% and 12.5% of patients in these corresponding groups who experienced immune-mediated AEs.

Any-grade AEs observed in more than 15% of patients in either treatment arm included pruritus (28.8%; 17.5%), rash (25.5%; 13.3%), decreased appetite (19.5%; 12.2%), cough (15.4%; 11.1%), and anemia (15.0%; 16.0%). Immune-mediated AEs observed in more than 5% of patients in at least one arm comprised rash (42.4%; 19.0%), hepatitis (20.2%; 17.1%), hypothyroidism (15.0%; 12.5%), infusion-related reactions (12.4%; 6.1%), hyperthyroidism (6.0%; 6.8%), adrenal insufficiency (5.6%; 0.12%), and pneumonitis (4.5%; 7.6%).

Although this study failed to meet its primary end points, the investigation of anti-TIGIT therapy plus checkpoint inhibition is still ongoing.

“[Two] phase 3 trials that involve the anti-TIGIT [agent] tiragolumab are still to read out,” Peters shared. “[These include] the SKYSCRAPER-03 trial [NCT04513925], which is looking at tiragolumab plus atezolizumab in consolidation after completion of definitive chemoradiation [in unresectable stage III NSCLC], and IMbrave152/SKYSCRAPER-14 [NCT05904886], which looks at [tiragolumab plus atezolizumab and bevacizumab (Avastin)] in metastatic hepatocellular carcinoma. [Additionally,] 3 important TIGIT inhibitors are still in phase 3 development: domvanalimab, rilvegostomig, and the bispecific [antibody] belrestotug. We are looking forward to seeing further data [with these agents].”

References

1. Peters S, Herbst R, Horinouchi H, et al. SKYSCRAPER-01: a phase III, randomized trial of tiragolumab (tira) + atezolizumab (atezo) versus placebo (pbo) + atezo in patients (pts) with previously-untreated PD-L1-high, locally advanced unresectable/metastatic NSCLC. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. CT051.
2. Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche. January 5, 2021. Accessed April 28, 2025. https://www.roche.com/media/releases/med-cor-2021-01-05