BERLIN — Adding tiragolumab, an anti-TIGIT monoclonal antibody, to the established combination of atezolizumab plus bevacizumab does not add any benefit for patients with untreated locally advanced or metastatic hepatocellular carcinoma (HCC), reveal interim results from IMbrave152.

These data “confirm the activity of atezolizumab plus bevacizumab in the management of this population, as well as the safety,” said Richard S. Finn, MD, professor of Medicine at the Geffen School of Medicine, University of California, Los Angeles, when presenting the findings at the European Society for Medical Oncology (ESMO) Annual Meeting 2025 on October 19.

Invited discussant Stephen L. Chan, MD, professor at the Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China, commented that, when he saw the survival curves for the study, he was “extremely disappointed.”

“But what makes me even a bit more disappointed” is that the earlier phase 1b/2 MORPHEUS-LIVER study suggested that adding tiragolumab to atezolizumab plus bevacizumab may be more clinically active than the doublet on its own in unresectable HCC, which is why IMbrave152, also known as SKYSCRAPER-14, was undertaken, he said.

Finn highlighted that the combination of atezolizumab and bevacizumab is an established first-line standard of care for patients with unresectable HCC, following the improvement in progression-free survival (PFS), objective response rate, and overall survival seen in IMbrave150 vs sorafenib, “with a very manageable and predictable safety profile.”

“Since that time, we’ve had other immunotherapy doublets approved that are improving outcomes for our patients,” he continued, “but still there are unmet needs in the frontline setting, as many patients do not get a benefit or eventually progress.”

Finn explained that TIGIT is a co-inhibitory receptor and immune checkpoint present on a number of activated immune cells and is implicated in several cancers, including HCC. As a human anti-TIGIT monoclonal antibody, tiragolumab is thought to be able to augment antitumor responses when combined with other immunotherapies.

Methods and Results

Patients were included in IMbrave152 if they were aged at least 18 years and had unresectable locally advanced or metastatic HCC, a good performance status, and received no prior systemic therapy for advanced disease. Systemic adjuvant therapy was allowed if the disease had recurred at least 6 months after treatment completion.

The participants were randomly assigned to atezolizumab and bevacizumab every 3 weeks plus either tiragolumab or placebo, with treatment continued until the loss of clinical benefit or unacceptable toxicity. No crossover was permitted. Patients underwent imaging follow-up approximately every 6 weeks.

Between September 14, 2023, and September 23, 2024, 669 patients were randomly assigned. The median age was 44.5 years, and 82.2% were men. The participants came from across the globe, including 1.5% from Africa and 9.4% from Central and South America.

Tumor cell PD-L1 expression ≥ 1% was present in 63.5% of cases. Finn pointed out that the patient population was “high risk,” adding: “Unlike other studies in advanced liver cancer, we did allow patients with main portal vein invasion, one of the worst prognostic factors in HCC.”

Presenting the results, he showed that the study did not meet its primary endpoint, however. There was no significant difference in PFS with the addition of tiragolumab to atezolizumab plus bevacizumab, at a median of 8.3 months vs 8.2 months for the doublet alone, with a hazard ratio of 0.97 (P = .7464).

Subgroup analysis did not reveal any patient groups who benefited from the triplet regimen, and there was little difference between the study arms in either the objective response rate, at 29.9% vs 26.0% with the doublet, or the duration of response, at 15.0 months vs 13.2 months.

Adding tiragolumab to atezolizumab plus bevacizumab increased the proportion of patients experiencing grade 3-4 adverse events, at 53.6% vs 47.7% with the doublet, and the rate of serious adverse events, at 45.8% vs 38.4%. Adverse events leading to any treatment withdrawal were also more common, at 17.8% vs 12.6%.

The most common adverse events in both treatment arms were proteinuria, hypertension, and pruritus. The most common adverse events of special interest seen with the triplet combination were immune-mediated hepatitis, rash, and infusion-related reactions.

Future Directions for Frontline Trials

Chan urged researchers to take a “more robust” approach to clinical trials, including for the control arm in phase 2, and consider the class effect of competitor drugs.

There have been a number of novel approaches in HCC that have not lived up to their billing, with the anti-LAG-3 antibody relatlimab, the bispecific antibody tebotelimab, which targets LAG-3 and PD-L1, and now tiragolumab performing poorly in recent trials.

However, there remains hope with rilvegostomig, a bispecific antibody against PD-1 and TIGIT, which is being explored in a combination regimen in ARTEMIDE-HCCO1, while the phase 2 AMBER study is looking at cobolimab, an anti-T-cell immunoglobulin and TIM-3 antibody, plus the anti-PD-1 dostarlimab in HCC.

“We’ve gone through 10 years without any drugs approved,” Chan said, but urged the audience to not “get too disappointed: there’s still many opportunities.”

The study was funded by F. Hoffmann-La Roche, Ltd.

Finn declared having relationships with Roche, Bristol Myers Squibb, Eisai, Merck, Pfizer, Roche/Genentech, AstraZeneca, Merck, Zai Labs, and Chugai.

Chan declared having relationships with AstraZeneca, Autum, Eisai, Eli Lilly and Company, Exelixis, GSK, Jiangsu Hengrui, HLB, HUTCHMED, Roche, Tempest, MSD, Celeron, Genor Biopharma, Chugai, Ipsen, Novartis, and Sirtex.