Hepatocellular carcinoma (HCC) is the most common primary liver tumor and remains a significant cause of cancer-related death globally. The incidence of HCC has been on the rise along with a proportionate rising trend in mortality.
- Sayiner M.
- Golabi P.
- Younossi Z.M.
Disease burden of hepatocellular carcinoma: a global perspective.
However, since the landmark sorafenib in advanced hepatocellular carcinoma (SHARP) trial of the efficacy of sorafenib in advanced HCC, there was little progress made in the armamentarium against advanced HCC for almost a decade. The advent of combination immunotherapy opened up a whole new paradigm in the management of HCC. The preliminary results of the IMbrave150 trial, which used a combination of the anti-programmed death-ligand 1 molecule atezolizumab with anti-vascular endothelial growth factor agent bevacizumab (A+B) marked an epoch in the timeline of HCC management. The results of the trial ultimately catapulted the position of the combination as a first-line therapy in the management of advanced HCC.
- Reig M.
- Forner A.
- Rimola J.
- et al.
BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update.
- Finn R.S.
- Qin S.
- Ikeda M.
- et al.
IMbrave150 investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.
At the time of publishing of the initial results of the IMbrave150 after a median 8.6 months of follow-up, the median overall survival (OS) which was one of the co-primary endpoints was not reached in A+B arm while it was 13.2 months with sorafenib, providing a significant reduction in the hazard for death [HR 0.58 (95% CI 0.42–0.79; P
< 0.001)]. The current study provided an updated post hoc analysis of the follow-up data from the IMbrave 150 trial.
Overall, in the trial, 501 patients were randomized to receive A+B (n = 336) or sorafenib (n = 165). At the time of analysis, 200 were discontinued in the A+ B arm (death = 179, rest lost to follow-up or withdrawal of consent) while 122 were discontinued in the sorafenib arm (death = 99, rest lost to follow-up or withdrawal of consent). The key results of the updated analysis show a median OS of 19.2 months (95% CI 17.0–23.7) in the A+B arm and 13.4 months (95% CI 11.4–16.9) in the sorafenib arm (P < 0.001). The 12 and 18-month survival rates were 67% and 52% with A+B and 56% and 40% with sorafenib. The second co-primary endpoint of the study was progression-free survival (PFS), which was defined as radiological progression or death. Similar to OS, A+ B showed a significantly better median PFS (6.9 months) than sorafenib (4.3 months). The beneficial results of A+B were consistent across various predefined subgroups, including crucial ones like BCLC stages (B and C), macrovascular invasion, extrahepatic spread, and PD-L1 status. The only subgroup in which the beneficial effect of A+B in OS was not seen was in HCC due to non-viral etiologies. A key area of interest with upcoming data of A+B is the adverse events with the combination. Similar to the initial IMbrave150 results, the most common treatment-related adverse events with A+B were proteinuria, hypertension, raised liver enzymes, and fatigue. Overall treatment-related grade 3/4 adverse events occurred in 43% and 46%, while grade 5 events occurred in 2% and <1% of patients in the A+ B and sorafenib arm. An important concern that has been raised with A+B combinations is the potential increased risk of bleeding. Overall, there were five grade 5 gastrointestinal bleeding events, of which only one was attributed to A+B.
This updated analysis demonstrates the longest median OS reported to date with any first-line therapy in treating unresectable HCC. Recent data from real-world studies have demonstrated similar findings, with an expansion of positive results even in patients with impaired liver function and those having received prior systemic therapy.
- de Castro T.
- Jochheim L.S.
- Bathon M.
- et al.
Atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma with impaired liver function and prior systemic therapy: a real-world experience.
While these promising results lead to an overall exciting time in the management of advanced HCC, some key areas of concern remain. One such domain is the lack of response in non-viral HCC, especially in the face of NASH becoming the driving force of liver disease and HCC globally. Furthermore, cost-effectiveness determinants and applicability in developing nations also remain a challenge to explore.
- Chiang C.L.
- Chan S.K.
- Lee S.F.
- Choi H.C.
First-line atezolizumab plus bevacizumab versus sorafenib in hepatocellular carcinoma: a cost-effectiveness analysis.
Hence, given the evidence available at this point of time, the combination therapy can be used as a first-line therapy in patients of advanced unresectable HCC, with preserved liver function (CTP-A), good performance status, and close monitoring for response assessment.
Conflicts of interest
Received in revised form:
© 2022 Indian National Association for Study of the Liver. Published by Elsevier B.V.