Analysis of common treatment-related adverse events of donafenib and its correlation with efficacy: exploratory analysis of the ZGDH3 study.
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BACKGROUND AND AIMS: Donafenib, a deuterium-modified sorafenib derivative, has improved survival outcomes in patients with advanced hepatocellular carcinoma (HCC). This study aimed to investigate the treatment-related adverse events and their associations with overall survival (OS) and time to progression (TTP) in patients with advanced HCC treated with donafenib. METHODS: In this retrospective analysis, data from 334 patients with unresectable or metastatic HCC who had a Child-Pugh liver function score ≤ 7 and had not received prior systemic treatment were collected from the ZGDH3 study. Donafenib (0.2 g) was administered orally twice daily until either intolerable toxicity or disease progression occurred. The associations between adverse events (AEs) and OS/TTP were analyzed using the Kaplan-Meier method, and statistical significance was tested using the log-rank test. A stratified Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CIs). RESULTS: Univariate analysis revealed that the median OS (mOS) was significantly longer in patients who experienced Grade 3 hand-foot skin reaction (HFSR), diarrhea, Grade ≥ 3 thrombocytopenia, hypertension, alopecia, rash, and proteinuria compared to those without these AEs (P < 0.05). Conversely, patients with fatigue and Grade ≥ 3 increased blood bilirubin had significantly shorter mOS than those without these AEs (P < 0.05). HFSR was associated with improved survival outcomes, with the mOS of patients with HFSR being 17.6 months, compared to 7.9 months in those without (HR = 0.498, 95% CI 0.384-0.648, P < 0.0001). The mOS was 14.2 months in patients with Grade ≥ 3 AEs, compared to 10.5 months in those without (HR = 0.687, 95% CI 0.442-0.802, P = 0.0061). There was no significant difference in the overall incidence of AEs between patients aged ≥ 65 and those < 65. CONCLUSIONS: The occurrence of HFSR, diarrhea, thrombocytopenia, hypertension, alopecia, rash, proteinuria, fatigue, and Grade ≥ 3 increased blood bilirubin may be associated with the efficacy of donafenib in the treatment of advanced HCC, though these are exploratory associations and not established predictive markers. The AEs associated with donafenib are generally well tolerated, though further validation is needed. TRIAL REGISTRY: NCT02645981.