Atezolizumab-bevacizumab combo continues to win in advanced HCC

The combination of the immune checkpoint inhibitor atezolizumab and the angiogenesis inhibitor bevacizumab continues to demonstrate significant clinical benefits vs the oral multikinase inhibitor sorafenib in patients with unresectable hepatocellular carcinoma (HCC), according to updated results from the IMbrave150 trial.

Similar benefits were seen in patients with high-risk HCC.

Median overall survival (OS) in the intention-to-treat (ITT) population (both high-risk and non–high-risk patients), was 19.2 months with atezolizumab-bevacizumab vs 13.4 months with sorafenib (p=0.0009). [AACR 2021, abstract CT009]

“The curves separated early and remained separated throughout the course of the study,” said lead author Dr Richard Finn from the Dr Geffen School of Medicine at the University of California, Los Angeles in Los Angeles, California US, who presented data from a median follow-up of 15.6 months.

“As a clinician treating HCC, I can’t tell you how exciting it was to see these [survival] curves, where you can see the superiority of the atezolizumab-bevacizumab combination over sorafenib, with early separation of the curves that last in both OS and PFS,” added discussant Dr Jennifer Knox from the Princess Margaret Cancer Centre at the University of Toronto, Ontario, Canada, during the AACR 2021 virtual meeting.

Efficacy and safety data by risk status

Finn presented updated results from a subgroup of 101 patients (64 in the atezolizumab-bevacizumab group and 37 in the sorafenib group) with high-risk disease who were from the original 501 patients in the ITT population.

High-risk disease was defined as tumour invasion of the main trunk of the portal vein and/or the portal vein branch contralateral to the primarily involved lobe (Vp4), and/or bile duct invasion and/or tumour occupancy of  ≥50 percent of the liver.

Of patients with high-risk HCC, 10 had bile duct invasion, 73 had Vp4 portal vein invasion, and 31 had liver tumour occupancy ≥50 percent. Nine patients in the atezolizumab-bevacizumab arm and 4 in the sorafenib arm had two high-risk factors.

At the clinical cut-off date, an efficacy benefit was observed for atezolizumab-bevacizumab regardless of the presence of high-risk features, said Finn.

Median OS, median PFS, and ORR all favoured atezolizumab-bevacizumab over sorafenib in high-risk patients (7.6 vs 5.5 months, 5.4 vs 2.8 months, and 16 vs 5, respectively). The same benefits were seen in non–high-risk patients.

“The HRs remained similar despite the numerical differences in median OS between non-high-risk and high-risk patients,” reported Finn. “In addition, the overall safety data in the atezolizumab-bevacizumab arm were comparable between non-high-risk and high-risk patients. They were also in line with the known safety profile of each drug.”

There were five fatal upper gastrointestinal bleeding events among high-risk patients treated with the combination therapy, but not one was treatment-related, Finn added. “Those who died had macrovascular invasion, suggesting that patients with such a high-risk feature are at increased risk for adverse events.”

Treatment-related adverse events of any grade, and grade 3 or 4 adverse events, occurred more frequently with sorafenib in both high-risk and non–high-risk patients. However, the incidence of serious adverse events was higher with the combination therapy in both high-risk and non–high-risk patients. As the duration of therapy was longer with atezolizumab-bevacizumab than with sorafenib, Finn said this could account for the higher incidence of serious adverse events with the combination therapy.

Post hoc OS analysis

Finn reported updated OS data for IMbrave150 at ASCO GI 2021, reflecting 12 months of additional follow-up after the primary analysis.

“The median survival for atezolizumab-bevacizumab is now over 19 months. This is the longest survival seen in a phase III study of advanced liver cancer,” said Finn during the virtual meeting. “This also confirmed atezolizumab-bevacizumab as a standard of care for previously untreated, unresectable HCC.”

At the clinical cut-off date of Aug 31, 2020, median follow-up was 15.6 months and 280 OS events were observed.  The 18-month OS rate was 52 percent with the combination vs 40 percent with sorafenib. Survival benefit with the combination therapy was generally consistent across subgroups and with the primary analysis. [J Clin Oncol 2021;39(suppl 3):267]

The 18-month PFS rates were 24 percent for the combination therapy vs 12 percent for sorafenib. The objective response rate (ORR; 29.8 percent per RECIST 1.1 criteria) with atezolizumab-bevacizumab was also in line with the primary analysis, with more patients achieving a complete response. The disease-control rate was 74 percent with the combination vs 55 percent with sorafenib. No new safety signals were observed over the course of follow-up.

What’s in the pipeline for HCC

Knoxx said other combination therapies are currently being explored for the first-line treatment of HCC. These include two trials with dual checkpoint inhibitors, and two comparing a tyrosine kinase inhibitor (TKI) plus checkpoint inhibitor with TKIs alone.

“There’s a lot of excitement about seeing these results … 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. “The current data for IMbrave has shown real benefit for both high- and the lower-risk patients, but clinicians need to be careful about the risk of haemorrhage in portal vein thrombosis.”

IMbrave150 was the first successful trial for a doublet therapy and the first positive randomized, phase III trial of an immune checkpoint inhibitor in the HCC space.  The combination strategy is also the first to improve survival over sorafenib monotherapy. [N Engl J Med 2020; 382:1894-1905]

Prior to IMbrave150, oncologists had only sorafenib to manage advanced HCC, and the clinical benefit was limited. IMbrave150 marked a breakthrough in the treatment of advanced HCC, offering patients the opportunity for improved disease control.

Atezolizumab-bevacizumab is now approved globally in patients with advanced or unresectable HCC who have not received prior systemic therapy.