The combination of atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor, plus bevacizumab, an anti-angiogenesis agent, significantly improved overall and progression-free survival (PFS) compared with sorafenib in treatment-naïve patients with unresectable hepatocellular carcinoma, the IMbrave150 phase III trial has shown.
At a median follow-up of 8.6 months, overall survival (OS) was 42% longer in the combination arm with 67.2% (95% CI, 61.3-73.1%) of patients still alive at 12 months compared with 54.6% (95% CI, 45.2-64.0%) of patients treated with sorafenib, Richard Finn, MD, Geffen School of Medicine at the University of California in Los Angeles and colleagues reported in The New England Journal of Medicine.
PFS was prolonged to a similar extent, being 41% longer at 6.8 months (95% CI, 5.7-8.3 months) for the same atezolizumab-bevacizumab combination compared with 4.3 months (95% CI, 4.0-5.6 months) in the sorafenib arm (P<0.001 for both end points), investigators added.
“These data are momentous, since they identify not only the first therapy to improve survival beyond sorafenib, but also the first successful combination regimen and the first positive randomized, phase III trial of immune checkpoint inhibition in this challenging cancer,” editorialist Robin Kelley, MD, University of California in San Francisco observed.
“The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma,” he underscored.
The intention-to-treat population included 336 patients in the atezolizumab plus bevacizumab arm and 165 patients in the single-agent arm. Importantly, this population included a subgroup of particularly high-risk patients including 40% of patients who had macrovascular invasion.
“Patients assigned to the atezolizumab-bevacizumab group received 1200 mg of atezolizumab plus 15 mg/kg of body weight of bevacizumab intravenously every 3 weeks,” researchers explained.
Those randomized to the sorafenib arm received 400 mg of the drug, orally, twice a day.
“Tumors were assessed by computed tomography or magnetic resonance imaging at baseline and every 6 weeks until week 54 and then every 9 weeks thereafter,” Finn and colleagues noted.
At 6 months, the estimated OS rate at 84.8% (95% CI, 80.9-88.7%) in the atezolizumab-bevacizumab arm was again considerably longer than it was in the sorafenib arm at 72.2% (95% CI, 65.1-79.4%), they added.
At 6 months, 54.5% of patients in the atezolizumab-bevacizumab group still had no disease progression compared with 37.2% of those in the sorafenib group.
At follow-up, 58.6% of patients on the PD-L1 inhibitor plus anti-angiogenesis combination had progressed or died as had 66.1% of those receiving single-agent sorafenib (P<0.001).
However, objective response rates — at 27.3% (95% CI, 22.5-32.5%) with atezolizumab-bevacizumab versus 11.9% (95% CI, 7.4-18%) — were significantly higher for the combination (P<0.001) while 5.5% of patients on the PD-L1 inhibitor plus anti-angiogenesis combination achieved a complete response compared to no patients in the sorafenib group.
Disease control rates comprised of objective response plus stable disease reached almost 74% with the atezolizumab-bevacizumab combination compared with 55.3% for sorafenib alone, the authors added.
“The estimated percentage of patients with duration of response longer than 6 months was 87.6% in the atezolizumab-bevacizumab group and 59.1% in the sorafenib group,” investigators observed.
The median time to deterioration on patient-reported quality of life measures was also 37% longer at 11.2 months for the combination versus only 3.6 months for sorafenib alone while the median time to deterioration in physical functioning was 47% longer at 13.1 months for the combination compared with a median of 4.9 months for sorafenib alone.
Adverse Events
“The most common grade 3 or 4 event with atezolizumab-bevacizumab was hypertension (15.2%), Finn and colleagues noted — an observation that is consistent with the known safety profile of bevacizumab.
Some 15.5% of patients in the combination group discontinued treatment because of adverse events (AEs) compared with 10.3% of those on sorafenib.
Gastrointestinal disorders were the most common cause for discontinuation in the PD-L1 inhibitor plus anti-angiogenesis arm.
This was to be expected in patients with liver cancer and underlying cirrhosis, while bleeding — including fatal bleeds — is a known adverse reaction to bevacizumab.
More grade 5 AEs also occurred in atezolizumab-bevacizumab-treated patients at 4.6% compared with 5.8% of sorafenib-treated patients, as did serious AEs at 38% in the combination group compared with 30.8% of those treated with sorafenib.
Commenting further on the study results, Kelley cautioned that patients enrolled in the current trial had to have Child-Pugh class A liver function, meaning their liver disease was well compensated.
Moreover, patients who were at high risk for bleeding or who had incompletely treated varices were excluded from the study.
“In the atezolizumab-bevacizumab group, bleeding of any grade attributed to bevacizumab occurred in 25.2% of the patients, whereas bleeding occurred in 17.3% of the patients who received sorafenib,” Kelley noted.
There were also 6 episodes of fatal bleeding or perforated ulcer in the combination group versus only one in the sorafenib group.
“Collectively, these findings underscore important considerations for the application of the atezolizumab-bevacizumab regimen to a broader population beyond the clinical trial setting,” Kelley emphasized.
“[And] all patients at risk for varices require appropriate endoscopic evaluation and management before treatment is initiated,” he stated, adding that since the safety of the combination has not been studied in patients with Child-Pugh class B disease, “alternative therapies should be considered for patients at high risk for bleeding.”
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The combination of a PD-L1 inhibitor plus an anti-angiogenesis agent significantly improved overall and progression-free survival compared with the current standard in treatment-naive patients with unresectable liver cancer.
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The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma.
Pam Harrison, Contributing Writer, BreakingMED™
The ImBRAVE study was supported by F. Hoffmann-La Roche/Genentech.
Finn reported consultant agreements with AstraZeneca, Bayer, Bristol-Myers Squibb, c.stone, Eiasai, Inc., Eli Lilly and company, Exelixis Inc., F. Huffmann-La Roche, Genentech USA, Inc., Merck, Novartis Pharma, and Pfizer.
Kelley reported grants from Agios, grants from Astra Zeneca, grants from BMS, grants from Bayer, grants from Eli Lilly, grants from EMD Serono, grants from Exelixis, grants from Merck, grants from Novartis, grants from QED, grants from Partner Therapeutics, grants from Taiho, non-financial support from Ipsen, personal fees from Gilead, and personal fees from Genentech/Roche outside the submitted work .
Cat ID: 935
Topic ID: 78,935,730,111,188,19,935,192
