medwireNews: In the MORPHEUS-Liver trial, the addition of tiragolumab to atezolizumab plus bevacizumab significantly improved the objective response rate (ORR) for patients with unresectable hepatocellular carcinoma, compared with standard therapy alone.
The triple therapy was also “not associated with substantial worsening of treatment-related or immune-mediated adverse events, and no new safety signals were identified,” write the authors in The Lancet Oncology.
They say that their “data suggest a positive benefit–risk ratio and are the basis for further investigation of tiragolumab plus atezolizumab plus bevacizumab as a novel first-line treatment option for patients with unresectable hepatocellular carcinoma.”
Richard Finn (University of California, Los Angeles, USA) and colleagues conducted a randomized, open-label, phase 1b–2 study at 26 centers across China, France, Israel, New Zealand, South Korea, Taiwan, and the USA.
Eligible patients were adults with previously untreated, locally advanced unresectable hepatocellular carcinoma, an ECOG performance status of 0–1, Child-Pugh class A disease, and a life expectancy of at least 3 months. The median age of the patients was 65 years, 79% were men, and the majority were Asian (40%) or White (36%).
The patients received atezolizumab 1200 mg plus bevacizumab 15 mg/kg with or without the anti-T cell immunoglobulin and ITIM domain (TIGIT) monoclonal antibody tiragolumab 600 mg every 3 weeks on day 1 of each 21-day cycle. Treatment continued until unacceptable toxic effects or loss of clinical benefit.
Among the 40 patients receiving tiragolumab therapy, 43% met the primary endpoint of a confirmed objective response at the time of clinical cutoff after a median of 20.6 months. This was significantly higher than the 11% rate at a median follow-up of 14.0 months among the 18 patients receiving atezolizumab plus bevacizumab alone. All the responses were partial in both treatment groups.
Adjunctive tiragolumab treatment was also associated with longer progression-free survival, at a median of 12.3 months versus 4.2 months without, with a significant hazard ratio for disease progression or death of 0.51 in favor of tiragolumab use.
In a comment on the study, Thomas Yau (The University of Hong Kong, China) and colleagues say that “[t]he results are undoubtedly exciting.”
However, they note that the small number of patients in the standard therapy group “probably contributed to the low observed objective response rate.” They also point out that there were “imbalances in a key prognostic factor,” with the atezolizumab plus bevacizumab group having twice as many patients with high alfa fetoprotein (≥ 400 ng/mL) as the adjunctive tiragolumab group (67 vs 33%).
The two treatment groups had similar rates of serious adverse events, occurring in 53% of patients receiving adjunctive tiragolumab and 56% of patients receiving atezolizumab plus bevacizumab, while rates of treatment-related serious adverse events were 25% versus 28%, most commonly gastrointestinal disorders.
There was one treatment-related death due to cholestasis among patients receiving tiragolumab and two due to esophageal varices hemorrhage and upper gastrointestinal hemorrhage in the standard therapy group.
Yau and co-authors note that “given the early-phase setting, these observed rates are somewhat unexpected,” but suggest that they might “be due to the small numbers of patients recruited.”
The researchers conclude that the findings “provide a rationale for further investigation of tiragolumab plus atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.”
They highlight the ongoing randomized, double-blind, placebo-controlled, phase 3 IMbrave152/SKYSCRAPER-14 study, which is assessing adjunctive tiragolumab treatment versus atezolizumab plus bevacizumab alone in patients with untreated locally advanced or metastatic hepatocellular carcinoma.
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