Data from the IMbrave050 study show benefits of atezolizumab plus bevacizumab in terms of disease recurrence, but long-term data are needed
Adjuvant therapy with the anti-PD-L1 atezolizumab plus the anti-VEGF bevacizumab showed to decrease the risk of disease recurrence or death of 28% compared to active surveillance in patients with resected or ablated hepatocellular carcinoma (HCC), according to the interim analysis results of the IMbrave050 study (Lancet. 2023 Oct 20:S0140-6736(23)01796-8).
Despite resection or ablation are potentially curative treatments for HCC, post-operative recurrence rates within 5 years are reported to exceed 70%, with higher rates in patients with a more advanced tumour burden (J Gastroenterol Hepatol. 2012 Jan;27(1):51-8). Currently, active surveillance is the standard of care and no other options are available in the adjuvant setting.
The phase 3, randomised, open-label IMbrave050 study involved 668 patients as intention-to-treat population from 134 hospital and medical centres in four regions, mostly from the Asia-Pacific region. All patients had a first diagnosis of HCC and had undergone either complete surgical resection (R0, grossly and microscopically negative margins) or ablation (microwave or radiofrequency ablation with complete response on imaging) within 4–12 weeks of random allocation to either the adjuvant treatment or active surveillance. Treatment in the experimental arm was 1200 mg intravenous atezolizumab plus intravenous bevacizumab 15 mg/kg every 3 weeks for up to 12 months or 17 cycles. The primary study endpoint was recurrence-free survival (RFS) as defined as time from randomisation to disease recurrence per independent review facility or death from any cause. Disease recurrence was evaluated with contrast enhanced CT or MRI at baseline, every 12 weeks (±7 days) from the date of random allocation for the first 3 years, and every 24 weeks thereafter (±10 days), regardless of treatment delays, until confirmation of disease recurrence by an independent review facility.
Results from the interim analysis showed a benefit in RFS in favour of the experimental arm (HR 0.72 (95% CI 0.53-0.98); p-value 0.012). Patients in the atezolizumab plus bevacizumab group had a 33% reduction in the risk of independent review facility-assessed disease recurrence compared with the active surveillance group (HR 0·67; 0·52–0·88; descriptive p=0·0030; appendix p 12).
“This is the first clinical trial showing a potential benefit of an adjuvant therapy with an acceptable toxicity profile in resected or ablated hepatocellular carcinoma, which could have potential impact on current standard of care”, says Dr Angela Lamarca, from Fundación Jiménez Díaz University Hospital, Madrid, Spain.
Despite encouraging, the study outcomes leave many questions unanswered according to Lamarca including the assessment of an adequate duration of adjuvant therapy with immunotherapy approaches and its potential impact on derived benefit. “Also, in the study there was a predominance of local recurrence, with a component of intrahepatic recurrence in above 65% of events of recurrence, which highlights the importance of differentiating actual recurrence from new primaries”, she explains. “Finally, a need of better define the target population has emerged, as the so-called ‘high risk of recurrence population’ as used by the study investigators is a new concept that will need validation in HCC setting.”
In the IMbrave050 study, overall survival (OS) data were immature at the time of data cut-off. “Around 60% of patients who had recurred in the study received atezolizumab and bevacizumab at time of recurrence, which may challenge the identification of an OS signal”, concludes Lamarca. “We could well be in front of a new standard of care, but further long-term data are likely to be required to elucidate the role of immunotherapy-based adjuvant therapy for HCC.”