Atezolizumab and Bevacizumab TRAEs are Potential Predictors of Favorable Outcomes in HCC

Patients with hepatocellular carcinoma (HCC) who developed treatment-related adverse effects (TRAEs) associated with atezolizumab (Tecentriq) plus bevacizumab (Avastin) had improved overall survival (OS) and progression-free survival (PFS) outcomes, according to findings from a retrospective study presented at the 16th Annual International Liver Cancer Association Conference Annual Conference.¹

Investigators concluded that the significant improvement in OS and PFS that occurred in patients treated with atezolizumab plus bevacizumab was 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 OS and 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 hazard ratio (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 multicenter 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 IMbrave150 trial (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/3S0BUDM
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