Abstract

Background:

Pragmatic endpoints, such as time-to-treatment discontinuation (TTD), defined as the duration from starting a medication to the date of treatment discontinuation or death, have been proposed as a potential efficacy endpoint for real-world practice. This study aims to analyze the frequency and severity of immune-related adverse events (irAEs) and TTD in patients with hepatocellular carcinoma (HCC) receiving Atezolizumab and Bevacizumab (A+B) treatment.

Methods:

This retrospective, multi-center study included consecutive HCC patients who received A+B treatment from September 2020 to December 2022. The primary endpoint of the study was the assessment of TTD and overall survival (OS). The associations of factors on outcomes were analyzed using Cox proportional hazards regression and multivariable logistic regression models.

Results:

The study included 150 HCC patients with a median age of 64 years. 85.3% were male, and 69.3% had viral hepatitis etiology. 52% had portal vein tumor thrombus (PVTT). Overall, 34.0% patients experienced grade 3 or higher treatment-related adverse events, with 20.0% reported irAEs. The incidence rates of irAEs were hepatitis (9.3%), colitis (3.3%), severe fatigue (2.0%), pneumonitis (2.0%), cholangitis (1.3%), skin rash (1.3%), myositis (0.7%), asthma (0.7%), and anaphylactic shock (0.7%). The median OS was 13.6 months (95% CI, 8.0-20.6) and the median progression-free survival was 5.7 months (95% CI, 4.0-12.5), while the median TTD was 3.6 months (95% CI, 2.6-5.1). Occurrence of irAEs, female gender, ALBI grade ≥2, Child-Pugh class B, and neutrophil-to-lymphocyte ratio (NLR) ≥3 and were found to be significantly associated with poor TTD in the univariate analysis. In the multivariate analysis, occurrence of irAEs (HR, 1.765; 95% CI, 1.108-2.813, p=0.004), ALBI grade ≥2 (HR, 1.639; 95% CI, 1.054-2.550, p=0.028) and female gender (HR, 1.687; 95% CI, 1.018-2.795, p=0.042) were identified as the independent predictor of TTD. For OS, the univariate analysis showed that irAEs, ALBI grade ≥2, Child-Pugh class B, NLR ≥3, PVTT and tumor size (≥7cm) were found to be significant. The occurrence of irAEs (HR, 2.423; 95% CI, 1.371-4.280, p=0.002), ALBI grade ≥2 (HR, 2.926; 95% CI, 1.511-5.667, p=0.001), Child-Pugh class B (HR, 2.685; 95% CI, 1.258-5.308, p=0.005), and PVTT (HR, 2.029; 95% CI, 1.159-3.552, p=0.013) were identified as the independent predictor of OS.

Conclusion:

In our multicenter retrospective cohort study, the combination therapy of A+B demonstrated significant efficacy. Our results highlight the importance of TTD as an important outcome measure, encompassing both disease progression and treatment discontinuation. We identified irAEs as an independent prognostic factor for A+B treatment. Thus, it is crucial to actively monitor and manage irAEs to optimize treatment outcomes.