New Combo Shows Benefit Even in Patients With High-Risk HCC

Neil Osterweil

April 14, 2021

Updated data continue to show significant clinical benefits for patients with unresectable hepatocellular carcinoma (HCC) with the combination of the immune checkpoint inhibitor atezolizumab (Tecentriq) and angiogenesis inhibitor bevacizumab (Avastin).

The new analysis shows benefit even in patients with high-risk disease.

The findings come from the practice-changing IMBRave150 trial, and the new data are from a median follow-up of 15.6 months. They show that median overall survival in the intention-to-treat (ITT) population, which included both high-risk and non–high-risk patients, was 19.2 months for patients randomized to atezolizumab-bevacizumab vs 13.4 months for patients on sorafenib (P = .0009).

Jennifer J. Knox, MD, from the Princess Margaret Cancer Centre at the University of Toronto, Ontario, Canada, commented that the updated data confirm her first impressions of the atezolizumab-bevacizumab combination.

"As a clinician who treats HCC, I can’t tell you how exciting it was to see these [survival] curves, now published in The New England Journal of Medicine, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both overall survival and progression-free survival," she said.

Knox was acting as a discussant for the presentation, where the new data were reported by Richard S. Finn, MD, from the Jonsson Comprehensive Cancer Center at the University of California Los Angeles. Both were speaking at the virtual annual meeting of the American Association for Cancer Research.

Benefit Seen Also in High-Risk Group

At the meeting, Finn reported results from a subgroup of 101 patients who had high-risk disease (from 501 patients in the ITT population).

High-risk disease included tumor invasion of the main trunk of the portal vein of the liver and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion, and/or tumor occupancy of at least 50% of the liver. Many of these patients would have been excluded from contemporary trials in HCC, Finn noted. 

In this subgroup of patients with high-risk disease, the median overall survival with atezolizumab-bevacizumab was 7.6 months, compared with 5.5 months with sorafenib. This difference translated into a hazard ratio (HR) for death of 0.62 for the combination, although the upper limit of the 95% confidence was 1.00, and therefore statistically not significant.

The overall survival benefit for high-risk patients was similar to that in the non–high-risk population of 400 patients (HR, 0.68; 95% CI 0.51 - 0.91), Finn commented. 

Median progression-free survival (PFS) among high-risk patients was 5.4 months vs 2.8 months with sorafenib, although this difference too was not significant, possibly because of the relatively small sample size.

"The data in this high-risk group is generally consistent with what we saw in the intent-to-treat population, and that is to say that atezo-bev has improved overall survival and PFS as compared to sorafenib, and a very similar objective response rate in this high-risk group as in the intent-to-treat population," he said.

However, there were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination, compared with none in the sorafenib arm. None of the deaths were considered by investigators to be treatment-related, Finn said. All five patients who died had microvascular invasion, suggesting that patients with these features are at especially elevated risk for adverse events, he noted.

Overall, there were 23 on-study deaths among patients who received the combination (10 high-risk and 13 non–high-risk patients), compared with 9 patients treated with sorafenib (3 high-risk and 6 non–high-risk). Six of the deaths in the combination arm were attributed to treatment vs 1 in the sorafenib arm.

Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib than with the combination in both high-risk and non–high-risk patients.

In both treatment groups, however, the incidence of serious adverse events was higher with the combination. Finn noted that the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, which could account for the higher incidence of serious adverse events with the combination.

What’s Next?

In her discussion, Knox noted that several other combinations are currently being explored for first-line treatment of HCC, including two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor plus checkpoint inhibitor with TKIs alone.

"There’s a lot of excitement about seeing these results, and I think when they read out in the next year or two, there will be a lot of cross-trial comparisons with patient groups and outcomes with the IMBRave150 data, which will be informative in choosing treatments for our patients," she said.

"This abstract has shown that there is real benefit across both the high- and the lower-risk patients, and that clinicians need to be careful about the risk of hemorrhage in portal vein thrombosis," Knox summarized.

The IMBRave150 trial is sponsored by F. Hoffmann-La Roche. Finn disclosed consulting activities for F. Hoffmann-La Roche, and institutional grant/research support from F. Hoffmann and others. Knox disclosed grant/research support from F. Hoffmann-La Roche and others, and consulting for Merck, Pfizer, and Esai.

American Association for Cancer Research (AACR) Annual Meeting 2021: Abstract CT009. Presented April 10, 2021.

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