Tiragolumab Regimen Misses PFS End Point in Hepatocellular Carcinoma

"These data, now from a double-blind, placebo-controlled study of over 600 patients, confirm the activity of atezolizumab plus bevacizumab in the management of this population, as well as the safety, and moving forward, we will hopefully learn a lot from the study on how to best decide to move forward in advancing care for our patients with HCC," according to study author Richard S. Finn, MD.

Patients with untreated locally advanced or metastatic hepatocellular carcinoma (HCC) experienced no additional benefit with tiragolumab plus atezolizumab (Tecentriq) and bevacizumab (Avastin), as the combination missed the co-primary end point of investigator-assessed progression-free survival (PFS), according to a presentation on data from the phase 3 IMbrave152/SKYSCRAPER-14 study (NCT05904886) at the European Society for Medical Oncology Congress 2025.

Patients treated with placebo plus atezolizumab and bevacizumab (n = 338) had an investigator-assessed median PFS of 8.2 months (95% CI, 7.0-9.7) vs 8.3 months (95% CI, 7.1-9.8) in patients treated with tiragolumab plus atezolizumab plus bevacizumab (HR, 0.97; 95% CI, 0.8-1.2; stratified log-rank P =.7464).

Overall survival (OS) data, at this time, remain immature, and are not anticipated to reach statistical significance, according to study authors.

“These data, now from a double-blind, placebo-controlled study of over 600 patients, confirm the activity of atezolizumab plus bevacizumab in the management of this population, as well as the safety, and moving forward, we will hopefully learn a lot from the study on how to best decide to move forward in advancing care for our patients with HCC,” study author and presenter, Richard S. Finn, MD, stated.

Finn is a professor of medicine at the David Geffen School of Medicine, UCLA, and director of the UCLA Liver Cancer Program.

Trial Design and Baseline Characteristics of the IMbrave152/SKYSCRAPER-14 Study

The IMbrave152/SKYSCRAPER-14 study is a double-blind, placebo-controlled, randomized global trial that enrolled 669 patients between September 14, 2023, and September 23, 2024. Eligible patients were 18 years or older with unresectable locally advanced or metastatic HCC, an ECOG performance status of 0 or 1, and Child-Pugh A liver function.

Patients were excluded from the study if they had received prior systemic therapy for advanced disease or experienced recurrence within 26 months of completing adjuvant treatment. Participants were randomized 1:1 to receive either tiragolumab 600 mg plus atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously every 3 weeks or placebo plus atezolizumab 1200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks.

Treatment continued until loss of clinical benefit or unacceptable toxicity, and crossover was not allowed. Imaging assessments were performed every 6 weeks, with a 1-week margin. Stratification factors included geographic region (Asia and Africa versus the rest of the world, including Japan), macroscopic vascular invasion (MVI) and/or extrahepatic spread (EHS; presence versus absence), baseline AFP level (≥400 ng/mL versus <400 ng/mL), and HCC etiology (viral versus non-viral).

The study’s primary end points were investigator-assessed PFS per RECIST v1.1 criteria and OS. Key secondary end points included objective response rate (ORR), duration of response (DOR), PFS and OS rates at select time points, safety, and patient-reported outcomes (PROs).

The baseline characteristics were generally well-balanced between the tiragolumab (n = 331) and the placebo (n=338) arms. The median age for all patients (n = 669) was 44.5 years, with 82.2% aged 65 years or older. The majority of patients were male (87.6% in both arms).

The most common geographic region was Asia/Asian Pacific/Australia (tiragolumab, 52.0%; placebo, 48.1%), followed by Europe and Middle East/North America (18.7%; 17.5%). Hepatitis B was the most frequent HCC etiology (65.6%; 59.8%), while 76.1% of all patients had an ECOG performance status of 0 or 1. The majority had Barcelona Clinic Liver Cancer (BCLC) stage B or C disease (75.9% overall) and a Child-Pugh score of A5 or A6 (63.5% overall).

Other key characteristics were similar: macrovascular invasion and/or extrahepatic spread was present in 36.7% of all patients, AFP levels of 400 ng/mL or higher in 25.9% of all patients, and 38.9% of the overall population had received prior local cancer therapy.

Exploratory Subgroup Analysis

An exploratory subgroup analysis of 909 patients showed that adding tiragolumab to atezolizumab plus bevacizumab was numerically associated with an improvement in median investigator-assessed PFS of 8.3 months versus 8.2 months (HR, 0.98; 95% CI, 0.8-1.2) compared to the atezolizumab plus bevacizumab arm.

Treatment benefit varied across prespecified baseline characteristics. Patients with baseline AFP less than 400 ng/mL appeared to derive the greatest benefit (HR, 0.74; 95% CI, 0.6-1.0), with a median investigator-assessed PFS of 9.8 months vs 5.5 months in the control arm. Conversely, patients with an ECOG performance score of 1, those in the Americas excluding Japan, those with high MVI and/or EHS (HR, 1.18; 95% CI, 0.9-1.5), and those with a Child-Pugh score A8 (HR, 1.18; 95% CI, 0.8-1.7) appeared to have a diminished or unfavorable treatment effect.

Median investigator-assessed PFS was longer in the experimental arm for nearly all subgroups, with notable exceptions including HCC etiology of hepatitis C (7.7 months versus 12.8 months) and the Child-Pugh A8 subgroup (4.7 months versus 5.7 months).

Understanding Additional Outcomes of the IMbrave152/SKYSCRAPER-14 Study

For the secondary end point of ORR, the ORR was 29.9% for the tiragolumab group with a complete response of 2.1% and a partial response of 27.8% vs 26.0% for the placebo group with a complete response of 1.8% and a partial response of 24.3%.

For DOR, among patients receiving the tiragolumab combination, there were 99 responders. Of these, 33.3% of patients experienced a subsequent event. The median duration of response was 15.0 months (range,13.9-not estimable [NE])

Among those receiving placebo, there were 88 responders. Of these, 38.6% experienced a subsequent event. The median duration of response was 13.2 months (range, 10.1-NE).

Stable disease was reported in 48.0% of the tiragolumab group vs 48.8% in the placebo group; progressive disease was reported in 16.3% versus 18.9% of patients, and the disease control rate (DCR) was 77.9% versus 74.9%, respectively.

How Safe is Tiragolumab Plus Atezolizumab and Bevacizumab?

The safety profile of the tiragolumab plus atezolizumab and bevacizumab combination (n = 332) was similar to the placebo plus atezolizumab and bevacizumab group (n = 333), though the tiragolumab arm experienced slightly higher rates of adverse events (AEs).

Nearly all patients in both arms reported AEs of any cause (tiragolumab, 98.8%; placebo, 97.6%). Grade 3/4 AEs were observed in 53.6%of patients of the tiragolumab-treated group and grade 5 AEs were seen in 8.4% vs 47.7% and 7.2% in the placebo group.

Serious AEs occurred in 45.8% of patients in the tiragolumab arm and 38.4% in the placebo arm. Drug-related AEs were reported in 92.8% and 87.1% of patients, respectively. AEs led to withdrawal of tiragolumab in 73.8% of patients receiving it (19.3%;1.5%), with 18.4% of those patients requiring systemic corticosteroids.

For bevacizumab, AEs resulted in withdrawal in 64.5% of the tiragolumab group (29.5%;3.3%) and 60.7% of the placebo group (22.2%;2.1%).

Disclosures: Prof. Richard S. Finn reported conflicts of interest with numerous pharmaceutical companies. He serves as a Principal Investigator for Merck/Eisai and Roche. He receives research funding from Bristol-Myers Squibb, Merck/Eisai, Pfizer, and Roche/Genentech. His roles as a speaker, consultant, or advisor involve relationships with AstraZeneca, Bristol-Myers Squibb, Chugai, Guerbet, Merck/Eisai, Novartis, Pfizer, Roche/Genentech, and Zai Labs. He is also a steering committee member for Bristol-Myers Squibb, Merck/Eisai, and Roche.

Reference

Finn RS, Singal AG, Cheng A, et al. IMbrave152/SKYSCRAPER-14: a phase III study of first-line tiragolumab + atezolizumab + bevacizumab vs placebo + atezolizumab + bevacizumab for patients with untreated locally advanced or metastatic hepatocellular carcinoma. Paper presented at: ESMO Congress; October 19, 2025; Berlin, Germany. Abstract LBA50.