Adjuvant atezolizumab plus bevacizumab significantly delays disease recurrence in hepatocellular carcinoma patients at high risk of recurrence after surgery or ablation

Results of the IMbrave050 study show that a combination of atezolizumab and bevacizumab as adjuvant treatment for hepatocellular carcinoma (HCC) patients with a high risk of recurrence after surgery or ablation results in a significantly longer, and clinically meaningful improvement in recurrence-free survival (RFS) compared to active surveillance. Importantly, this adjuvant treatment proved to be tolerable and did not have a detrimental effect on the quality of life (QoL) of patients. As such, these findings mark IMbrave50 as the first phase III study to demonstrate an RFS improvement following curative intent therapy in patients with HCC.

Background

The risk for postoperative recurrence in patients with HCC is high, with about two third of patients suffering a recurrence within 5 years. This risk is even more pronounced in patients with high-risk features, such as a large tumor size, multiple tumors, a poor tumor differentiation and vascular invasion. Interestingly, recurrences in patients with HCC occur in a bimodal pattern, with a first wave of recurrences within the first two years following curative treatment and a second wave after 4-5 years. To date, there is no adjuvant strategy to mitigate this recurrence risk in HCC patients. To address this medical need, the randomized-controlled, phase III IMbrave050 study assessed the potential of atezolizumab in combination with bevacizumab (atezo+bev) as adjuvant treatment for HCC patients at a high risk of recurrence following curative intent therapy. During ASCO 2023, updated RFS results of this study were presented together with patient reported outcome (PRO) data.

Study design

The phase III IMbrave050 trial enrolled 668 HCC patients at a high risk of recurrence following resection or ablation. These high-risk features included a tumor size of >5cm, the presence of more than 3 tumors, microvascular or minor macrovascular involvement, or a grade 3/4 pathology. Patients in the study were randomized to receive atezo+bev or were put under active surveillance. Patients in the experimental arm received intravenous atezo (1200 mg) + bev (15 mg/kg) every 3 weeks for a total of one year (17 cycles). Patients in the control arm underwent active surveillance for one year and were eligible to crossover to atezo+bev following recurrence. The primary endpoint of the study was RFS, with a change from baseline in global health status (GHS)/ quality of life (QoL), physical functioning, role functioning, emotional functioning, and social functioning as pre-specified exploratory endpoints.

Results

The median age of patients in the study was 60 years, with about four out of five patients being male. The majority of patients (~80%) had an Asian ethnicity and about three quarters had a viral HCC etiology. At diagnosis, 93% of patients had BCLC stage A or B disease. Across both study arms, 88% of patients were treated with surgery, while the tumor was ablated in the remaining 12%. Among patients who were surgically treated, the median longest diameter of the largest tumor was about 5.5 cm, while this was 2.5 cm in ablated patients.

At a median follow-up of 17.4 months, adjuvant atezo-bev was associated with a significantly better RFS compared to active surveillance, with a 12-months RFS rate of 78% and 65% for atezo-bev and active surveillance, respectively (median not reached for either arm; HR[95%CI]: 0.72[0.56-0.93]; p= 0.012). This RFS benefit did come at the cost of a higher incidence of grade ≥3 (42% vs. 13.3%) and serious adverse events (AEs) (24.1% vs. 10.3%). In the atezo-bev arm, 2 treatment-related grade 5 AEs were reported. AEs led to the interruption of any study drug in 46.7% of patients in the atezo-bev arm, with a complete withdrawal of any study drug in 19% of patients. However, this increased toxicity did not seem to have an important impact on the QoL of patients. In fact, the mean scores at baseline in both arms were high and similar, as measured by the GHS/QoL and physical, role, emotional and social functioning scales. Mean changes from baseline were not considerable through cycle 17 and were similar between both treatment arms. The GHS/QoL and functioning of patients was maintained through cycle 17, without a clinically meaningful deterioration at any time.

Conclusions

IMbrave050 is the first positive phase III study in HCC demonstrating a significant, and clinically relevant improvement with an adjuvant treatment following surgery or ablation. In fact, a statistically significant improvement in RFS was seen in high-risk HCC patients receiving atezo+bev compared to active surveillance. Overall, the safety profile of atezo+bev was manageable and in line with the established safety profiles of the individual agents and the underlying disease. The PRO outcome analyses revealed that treating high-risk HCC patients with adjuvant atezo+bev following procedures with curative intent did not result in a clinically meaningful deterioration in QoL or function.

Reference

Kudo M, et al. Efficacy, safety and patient reported outcomes (PROs) from the phase III IMbrave050 trial of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following re- section or ablation. Presented at ASCO 2023; Abstract 4002.