IMbrave050 is the first phase III study of adjuvant treatment for hepatocellular carcinoma (HCC) to report positive results. At the prespecified interim analysis, results show that adjuvant treatment with atezolizumab plus bevacizumab conferred a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS), compared with active surveillance, in patients with HCC at high risk of recurrence following curative-intent liver resection or local ablation.
These findings, coupled with a safety profile that was consistent with previous studies, suggest that the combination of atezolizumab plus bevacizumab offers a promising adjuvant treatment option in this setting according to Prof. Pierce K H Chow of the National Cancer Centre Singapore in Singapore, and colleagues who published the results on 20 October 2023 in The Lancet.
HCC usually occurs in the setting of liver cirrhosis because of chronic hepatitis B or C infections, non-alcoholic steatohepatitis, alcohol consumption, or diabetes. HCC with non-viral causes is becoming more frequent in western countries. The authors explained in the background that growing global incidence of HCC, coupled with the high probability of tumour recurrence after curative-intent treatment, highlights the need for effective adjuvant treatment options. However, there is no standard-of-care adjuvant treatment option for patients with HCC.
Atezolizumab combined with bevacizumab is the first-line standard-of-care for unresectable HCC based on results from the IMbrave150 study, which showed superior overall survival (OS), progression-free survival, and objective response rates with atezolizumab plus bevacizumab compared with sorafenib. These data provide a rationale for exploring this combination regimen in an earlier treatment setting. In IMbrave050, the study investigators evaluated the efficacy and safety of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with HCC at high risk of recurrence following curative-intent resection or ablation.
In the global, open-label, phase III IMbrave050 study, adult patients with high-risk surgically resected or ablated HCC were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was RFS by independent review facility assessment in the intention-to-treat (ITT) population.
The ITT population included 668 patients randomly assigned between 31 December 2019 and 25 November 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis on 21 October 2022, median duration of follow-up was 17.4 months. Adjuvant atezolizumab plus bevacizumab was associated with significantly improved RFS (median, not evaluable [NE]; 95% confidence interval [CI] 22.1–NE]) compared with active surveillance (median, NE [21.4–NE]); hazard ratio 0.72 (adjusted 95% CI 0.53–0.98; p = 0.012).
Grade 3 or 4 adverse events occurred in 136 of 332 patients (41%) who received atezolizumab plus bevacizumab and 44 of 330 patients (13%) in the active surveillance group. Grade 5 adverse events occurred in 6 patients (2%), two of which were treatment related in the atezolizumab plus bevacizumab group, and 1 patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab.
The authors commented that most patients were recruited from the Asia-Pacific region, primarily China, compared with the USA and Europe but based on tumour burden and staging, the patients enrolled reflect real-world data on surgical resection for HCC globally, and are aligned with major treatment guidelines for resection or ablation in both western and Asian countries. Consistent with other recent global HCC studies, enrolment of patients from under-represented minority groups was poor. Longer follow-up for both RFS and OS is needed to assess the benefit–risk profile more fully.
In an accompanied comment, Prof. Arndt Vogel of Toronto General Hospital, UHN and Princess Margaret Cancer Centre, both in Toronto, ON, Canada and Hannover Medical School in Hannover, Germany, and colleagues wrote that implementation of immune checkpoint inhibitors in the adjuvant setting raises some questions. In particular, the effect of adjuvant treatment on tumour biology, including pattern of recurrence and post-recurrence survival, is not defined in HCC.
The commentators recognise IMbrave050 as a milestone in the treatment of HCC, but they would not consider yet adjuvant atezolizumab and bevacizumab as practice-changing at this early timepoint of the first interim analysis. The benefit of the adjuvant treatment is restricted to a subgroup of patients. To improve patient stratification, and to align clinical observations with molecular correlates, investing in the translational programme would be highly valuable. Forthcoming data from ongoing phase III studies will help to clarify the benefit of immunotherapy-based adjuvant treatment and to also delineate the role of bevacizumab and to better define the target population.
The study was funded by F Hoffmann-La Roche/Genentech.
