Real-World Data Show TRAEs Associated With Improved Survival With Atezolizumab plus Bevacizumab in HCC

A multicentre, retrospective study showed that treatment-related adverse effects (TRAEs) associated with atezolizumab (Tecentriq) plus bevacizumab (Avastin) were prognostic of improvements in survival outcomes in patients with hepatocellular carcinoma (HCC). Findings were presented at the 16th Annual International Liver Cancer Association Conference Annual Conference.¹

Investigators concluded that the significant improvement in overall survival (OS) and progression-free survival (PFS) occurred in patients treated with atezolizumab plus bevacizumab associated with the development of any atezolizumab-related AE and hypertension as well as proteinuria from bevacizumab. Although more prospective studies are needed to further investigate and validate these findings, in a biomarker-deprived context, TRAEs can serve as potential predictors of prognosis.

Specifically, TRAEs were correlated with improved overall survival (OS) and progression-free survival (PFS) outcomes according to Cox proportional-hazards regression models. A total of 371 patients were eligible for inclusion in the analysis. Any-grade TRAEs were reported for 67% of patients and grade 3 to 5 TRAEs were recorded in 21% of patients.

For atezolizumab, 44% of patients experienced any grade of TRAEs, 9% of which were grade 3 to 5 events. Bevacizumab-related TRAEs were reported in 47% of patients and 14% were grade 2 to 5 events.

For PFS, the HR for patients who experienced an atezolizumab-related AE of any grade vs those who did not was 0.50 (95% CI, 0.36-0.69; P < .001). The HR for grade 3 to 5 events was 0.66 (95% CI, 0.34-1.27; P = .21).

Patients who had bevacizumab-related TRAEs vs those who did not the HR was 0.59 (95% CI, 0.44-0.80; P < .001) and 0.52 (95% CI,0.34-1.27; P = .003) for grade 3 to 5 TRAEs. HRs for bevacizumab any-grade TRAEs were as follows: hypertension, 0.52 (95% CI, 0.37-0.74; P < .001), proteinuria, 0.48 (95% CI, 0.34-0.68; P < .001), and thrombosis/bleeding, 0.88 (95% CI, 0.59-1.32; P = .54).

The HR for OS among patients with any-grade TRAEs treated with atezolizumab vs those who had no TRAEs was 0.62 (95% CI, 0.40-0.95; P = .028) and 0.65 (95% CI, 0.44-0.98; P = .04) for any-grade bevacizumab-related TRAEs.

The HRs for PFS for patients who received bevacizumab and had any-grade AEs were as follows:

1. Hypertension: 0.64 (95% CI, 0.42-0.96; P =.033)
2. Proteinuria, 0.57 (95% CI, 0.35-0.91; P = .02)
3. Thrombosis and bleeding, 1.17 (95% CI, 0.70-1.95; P = .56)

The OS HRs for patients who had grade 3 to 5 TRAEs vs those who have not were 1.02 (95% CI, 0.43-2.41; P = .97) for atezolizumab and 0.80 (95% CI, 0.46-1.40; P = .44) for bevacizumab.

The HRs for OS for patients who received bevacizumab and had grade 3 to 5 AEs were as follows:

1. Hypertension: 0.56 (95% CI, 0.21-1.54; P =.26)
2. Proteinuria, 0.13 (95% CI, 0.02-1.04; P = .055)
3. Thrombosis and bleeding, 1.67 (95% CI, 0.91-3.06; P = .099)

In the analysis, most eligible patients were men (84%) with a median age of 66 years. Patients were excluded if they had previous systemic treatments or Child-Pugh C status. Data were collected from 2019 to 2021 and came from 14 centers in Europe (n = 11), the US (n = 86), and Asia (n = 236).

The most common cause of disease was chronic viral hepatitis 64%. In terms of disease status, 72% of patients had Barcelona Clinic Liver Cancer disease and 80% had Child-Pugh A disease status and 20% of patients had Child-Pugh B status.

HCC is a leading cause of cancer death around the world and the standard of care for over 10 years was first-line sorafenib (Nexavar), which had historic median OS of 10 to 12 months in phase 3 studies. Atezolizumab plus bevacizumab was approved May 29, 2020, for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy based on the global, open-label phase 3 trial IMbrave150 (NCT03434379).2,3

In the trial, patients received atezolizumab plus bevacizumab (n = 336) or sorafenib (n = 165) from March 15, 2018, to January 30, 2019.Per RECIST 1.1 criteria the overall response rate (ORR) was 28% in the atezolizumab plus bevacizumab group vs 12% in the sorafenib group. The estimated median PFS was 6.8 months (95% CI, 5.8-8.3) vs. 4.3 months (95% CI, 4.0-5.6), respectively (HR, 0.59; 95% CI, 0.47-0.76; P < .0001).

Updates from the trial performed 12 months after the primary analysis showed a 5.8 month longer median OS with atezolizumab plus bevacizumab vs sorafenib. The ORR was 30% with the doublet with a median duration of response of 18.1 months. After a median follow-up of 15.6 months (range, 0-28.6), the median OS was 19.2 months (95% CI, 17.0-23.7) with atezolizumab plus bevacizumab and 13.4 months (95% CI, 11.4-16.9) with sorafenib (HR, 0.66; 95% CI, 0.52-0.85; descriptive P < .001). At 12 and 18 months, respectively, survival rates were 67% and 52% in the atezolizumab plus bevacizumab group and 56% and 40% patients in the sorafenib arm.

IMbrave150 data showed grade 3/4 TRAEs occurred in 43% of safety evaluable patients (n = 329) in the atezolizumab plus bevacizumab group and 46% of safety evaluable patients (n = 156) in the sorafenib arm.

References

1. D’Alessio A, Cheon J, Fulgenzi CAM, et all. Treatment-related adverse events and improved survival with atezolizumab plus bevacizumab; a global, real-world study. Poster presented at: 16th Annual International Liver Cancer Association Conference; September 1-4, 2022; Madrid, Spain. Accessed September 7, 2022. https://bit.ly/3RrpXHf
2. Casak SJ, Donoghue M, Fashoyin-Aje L, et al. FDA approval summary: atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma. Clin Cancer Res. 2021;27(7):1836-1841. doi:10.1158/1078-0432.CCR-20-3407
3. Cheng AL, Qin S, Ikeda M, et all. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4)862-873. doi:10.1016/j.jhep.2021.11.030