Beyond side effects: treatment-related adverse events are associated with improved survival outcomes in HCC patients on atezolizumab-bevacizumab therapy

Atezolizumab plus bevacizumab (Atez/Bev) is the first-line treatment for unresectable hepatocellular carcinoma (HCC). This study investigated the association of adverse events (AEs) with clinical outcomes by treatment relation, organ systems, and severity. This exploratory post hoc analysis included 435 HCC patients treated with Atez/Bev, 136 patients with sorafenib, and 58 patients with atezolizumab monotherapy from the IMbrave150 (NCT03434379) and GO30140 (NCT02715531) trials. Kaplan-Meier analysis was applied to estimate overall survival (OS) in patients treated with Atez/Bev for ≥ 3 months. Landmark analysis at 3 months restricted the OS analysis to 332 patients who completed ≥ 3 months of Atez/Bev. Among these patients, treatment-related renal/urinary, mild vascular, and skin/subcutaneous AEs were associated with improved OS compared with patients without the corresponding AE (mOS: not reached vs. 20.2 months, p < 0.001; not reached vs. 20.2 months, p < 0.001; and not reached vs. 22.8 months, p = 0.014, respectively). Experiencing one (HR = 0.56, 95% CI: 0.38, 0.81) or ≥ 2 types (HR = 0.20, 95% CI: 0.11, 0.37) of positively associated AEs demonstrated progressively improved OS. However, metabolism/nutrition, hepatobiliary, and grade 3 + gastrointestinal AEs were associated with poorer OS, with HRs at 1.58 (95% CI: 1.10, 2.26), 1.67 (95% CI: 1.08, 2.69) and 2.09 (95% CI: 1.28, 3.41), respectively. Atez/Bev-related renal/urinary, skin/subcutaneous, and mild vascular AEs were associated with favorable survival outcomes in HCC, whereas metabolism/nutrition, hepatobiliary, and severe gastrointestinal AEs were associated with poorer outcomes. These findings may help improve the interpretation of AEs during Atez/Bev treatment and inform individualized toxicity management.