Atezolizumab-bevacizumab combination provides ‘longest survival seen’ in advanced HCC
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Atezolizumab plus bevacizumab conferred the longest OS seen in a phase 3 study for treatment-naive advanced hepatocellular carcinoma, according to updated results of the IMbrave150 study presented at Gastrointestinal Cancers Symposium.
Richard S. Finn, MD, professor of medicine in the department of medicine, division of hematology/oncology, at David Geffen School of Medicine at UCLA, reported median OS of 19.2 months with atezolizumab (Tecentriq, Genentech/Roche) and bevacizumab (Avastin, Genentech) compared with 13.4 months with sorafenib (Nexavar, Bayer).
“This is the longest survival seen in a phase 3 study of advanced liver cancer, and this is supported by an improvement in PFS,” Finn said during his virtual presentation.
The combination of atezolizumab and bevacizumab received FDA approval for patients with unresectable HCC who had not received prior systemic therapy based on the primary analysis of this study, previously published in The New England Journal of Medicine. At the time of that report, based on median follow-up of 8.6 months, the combination conferred statistically significant improvements in OS (HR = 0.58; 95% CI, 0.42-0.79) and PFS (HR = 0.59; 95% CI, 0.47-0.76). However, median OS for the combination had not yet been reached.
Finn reported updated data from the trial after median follow-up of 15.6 months.
The analysis included 501 patients randomly assigned 2:1 to receive 1,200 mg IV atezolizumab every 3 weeks plus 15 mg/kg IV bevacizumab every 3 weeks (n = 336; median age, 64 years; range, 26-88; 82% men) or 400 mg twice-daily sorafenib (n = 165; median age, 66 years; range, 33-87; 83% men).
All patients had unresectable HCC for which they had not received systemic therapy, Child-Pugh class A liver function and ECOG performance status of 0 or 1. Most patients also had high-risk features including alpha fetoprotein of 400 ng/mL or higher (combination, 38%; sorafenib, 27%), extrahepatic spread (combination, 63%; sorafenib, 56%) and macrovascular invasion (combination, 38%; sorafenib, 43%).
OS and PFS, assessed by independent review, served as the study’s co-primary endpoints.
At the time of the updated analysis, 74% of patients assigned sorafenib had gone off study, compared with 60% of those assigned the atezolizumab-bevacizumab combination. The most common reason for study discontinuation was death (sorafenib, 60%; atezolizumab-bevacizumab, 53%).
Updated survival data showed median OS of 19.2 months with the combination vs. 13.4 months with sorafenib (HR = 0.66; 95% CI, 0.52-0.85).
Median PFS was 6.9 months with the combination vs. 4.3 months with sorafenib (HR = 0.65; 95% CI, 0.53-0.81).
Updated response data showed a confirmed overall response rate per RECIST version 1.1 criteria of 30% with the combination vs. 11% with sorafenib, with complete response rates of 8% vs. less than 1%, disease control rates of 74% vs. 55%, and median duration of response of 18.1 months (95% CI, 14.6 to not estimable) vs. 14.9 months (95% CI, 4.9-17).
The response patterns were similar when measured using HCC-modified RECIST version 1.1 criteria, Finn said.
“We see with longer follow-up that we have more responses with atezolizumab-bevacizumab than initially reported,” he said. “The response rate ... includes more complete responses.”
A greater proportion of patients assigned sorafenib progressed and received additional treatment than those assigned the combination (52% vs. 36%). About one-third of patients received tyrosine kinase inhibitors as subsequent treatment, and 26% of patients assigned sorafenib subsequently received immunotherapy.
Finn also reported survival data from a cohort of 137 Chinese patients from the intent-to-treat population and 57 Chinese patients enrolled in an extension cohort. Of them, 133 (median age, 57 years; range, 29-82; 87% men) received atezolizumab-bevacizumab and 61 (median age, 60 years; range, 31-82; 80% men) received sorafenib.
A majority of patients in both groups had hepatitis B-related HCC (combination, 88%; sorafenib, 77%).
Median OS for this cohort reached 24 months with the combination vs. 11.4 months with sorafenib (HR = 0.53; 95% CI, 0.35-0.8).
Finn said there were no new safety signals at the time of the updated analysis; however, there was an increase in treatment-related grade 3 to grade 4 adverse events, which occurred in 63% of patients assigned the combination vs. 57% assigned sorafenib.
“This increase is likely reflecting the fact that patients have been on treatment longer,” Finn said.
Perspective
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The updated results of IMbrave 150 reported by Finn and colleagues confirmed the benefits of atezolizumab-bevacizumab as initial therapy for patients with advanced, unresectable HCC in comparison with sorafenib. The authors also observed benefits in a Chinese population, which had a predominantly hepatitis B etiology of HCC, as well as in the global population and etiologies more common in the West, including hepatitis C and nonviral etiologies that represented about half of the overall IMbrave 150 population.
Therefore, atezolizumab-bevacizumab represents the reference standard for patients with good hepatic function, recognizing that for enrollment in the study, patients had to be demonstrated to be at low risk for variceal bleeding by esophagogastroduodenoscopy prior to enrollment, which is not always done clinically.
This dramatic shift in our management of unresectable HCC has upended our prior treatment paradigm in the past year, and clinicians and investigators are scrambling to better understand how to continue to improve outcomes of these patients. Prominent areas of exploration include the evaluation of combinations of checkpoint inhibitors, with Wong and colleagues reporting some promising retrospective results combining the anti CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) with the anti-PD-1 antibodies nivolumab (Opdivo, Bristol Myers Squibb) or pembrolizumab (Keytruda, Merck), and approved (albeit after sorafenib) VEGFR inhibitors either alone or in combination with immunotherapy. However, the optimal approach in the second-line setting remains unclear, rendering this area fraught with uncertainty and opportunity.
Reference:
Wong JSL, et al. Abstract 330. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan 15-17, 2021.
Levine Cancer Institute at Atrium Health
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Finn RS, et al. Abstract 267. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan. 15-17, 2021.
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