Tiragolumab Treatment Combo Misses Mark in Advanced Liver Cancer

Adding Tecentriq (atezolizumab) to Tecentriq plus Avastin (bevacizumab) and tiragolumab treatment did not show an added benefit in patients with untreated locally advanced or metastatic hepatocellular carcinoma, according to data from a phase 3 study presented during the 2025 ESMO Congress. The co-primary end point of investigator-assessed progression-free survival was missed.

Patients treated with placebo plus Tecentriq and Avastin (338 patients) had an investigator-assessed median progression-free survival of 8.2 months versus 8.3 months in patients treated with tiragolumab plus Tecentriq plus Avastin. Overall survival data 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 Tecentriq plus Avastin 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 hepatocellular carcinoma,” study author and presenter, Dr. Richard S. Finn, stated. Dr. Finn is a professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles, and director of the UCLA Liver Cancer Program.

Trial Design and Baseline Characteristics

The 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 hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and Child-Pugh A liver function.

Patients were excluded if they had received prior systemic therapy for advanced disease or experienced recurrence within 26 months of completing adjuvant treatment. Participants were randomized one-to-one to receive either tiragolumab six hundred milligrams plus Tecentriq one thousand two hundred milligrams plus Avastin fifteen milligrams per kilogram intravenously every three weeks or placebo plus Tecentriq one thousand two hundred milligrams and Avastin fifteen milligrams per kilogram intravenously every three weeks.

Treatment continued until loss of clinical benefit or unacceptable toxicity, and crossover was not allowed. Imaging assessments were performed every six weeks, with a one-week margin. Stratification factors included geographic region (Asia and Africa versus the rest of the world including Japan), macroscopic vascular invasion and/or extrahepatic spread, baseline alpha-fetoprotein level (≥400 nanograms per milliliter versus <400 nanograms per milliliter), and hepatocellular carcinoma etiology (viral versus non-viral).

The study’s primary end points were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 criteria and overall survival. Key secondary end points included objective response rate, duration of response, progression-free survival and overall survival rates at select time points, safety, and patient-reported outcomes.

Baseline characteristics were generally well-balanced between the tiragolumab (331 patients) and the placebo (338 patients) arms. The median age for all patients (669 patients) was 44.5 years, with 82% aged 65 years or older. The majority were male (87.6% in both arms).

The most common geographic region was Asia/Asian Pacific/Australia (tiragolumab, 52%; placebo, 48.1%), followed by Europe and Middle East/North America (18.7%; 17.5%). Hepatitis B was the most frequent hepatocellular carcinoma etiology (65.6%; 59.8%), while 76.1% of all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The majority had Barcelona Clinic Liver Cancer 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, alpha-fetoprotein levels of 400 nanograms per milliliter 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 Tecentriq plus Avastin was numerically associated with an improvement in median investigator-assessed progression-free survival of 8.3 months versus 8.2 months compared to the Tecentriq plus Avastin arm.

Treatment benefit varied across prespecified baseline characteristics. Patients with baseline alpha-fetoprotein less than 400 nanograms per milliliter appeared to derive the greatest benefit, with a median investigator-assessed progression-free survival of 9.8 months versus 5.5 months in the control arm. Conversely, patients with an Eastern Cooperative Oncology Group performance score of 1, those in the Americas excluding Japan, those with high macroscopic vascular invasion and/or extrahepatic spread, and those with a Child-Pugh score A8 appeared to have a diminished or unfavorable treatment effect.

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

Additional Outcomes

For the secondary end point of objective response rate, the rate was 29.9% for the tiragolumab group with a complete response of 2.1% and a partial response of 27.8% versus 26% for the placebo group with a complete response of 1.8% and a partial response of 24.3%.

For duration of response, among patients receiving the tiragolumab combination, there were 99 responders. Of these, 33.3% experienced a subsequent event. The median duration of response was 15 months. Among those receiving placebo, there were 88 responders, with 38.6% experiencing a subsequent event. The median duration of response was 13.2 months.

Stable disease was reported in 48% of the tiragolumab group versus 48.8% in the placebo group; progressive disease was reported in 16.3% versus 18.9% of patients, and the disease control rate was 77.9% versus 74.9%.

Safety

The safety profile of the tiragolumab plus Tecentriq and Avastin combination (332 patients) was similar to the placebo plus Tecentriq and Avastin group (333 patients), though the tiragolumab arm experienced slightly higher rates of side effects. Nearly all patients in both arms reported side effects of any cause (tiragolumab, 98.8%; placebo, 97.6%). Grade 3 (severe)/4 (life-threatening) side effects were observed in 53.6% of patients in the tiragolumab group and grade 5 side effects were seen in 8.4% versus 47.7% and 7.2% in the placebo group.

Serious side effects occurred in 45.8% of patients in the tiragolumab arm and 38.4% in the placebo arm. Drug-related side effects were reported in 92.8% and 87.1% of patients, respectively. Side effects led to withdrawal of tiragolumab in 73.8% of patients receiving it, with 18.4% of those patients requiring systemic corticosteroids. For Avastin, side effects resulted in withdrawal in 64.5% of the tiragolumab group and 60.7% of the placebo group.

Reference

1. “IMbrave152/SKYSCRAPER-14: a phase 3 study of first-line tiragolumab plus Tecentriq plus Avastin versus placebo plus Tecentriq plus Avastin for patients with untreated locally advanced or metastatic hepatocellular carcinoma” by Dr. Richard S. Finn, et al., presented at ESMO Congress.

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