Cabozantinib (CAB) causes a high incidence of adverse events in unresectable hepatocellular carcinoma (u-HCC) and requires dose adjustments. We evaluated the efficacy and safety of the 7-on/7-off regimen composed of 7 consecutive days’ administration of CAB followed by a 7-day rest period. This was a retrospective analysis of 35 patients with u-HCC, who were treated with CAB in a multicenter cohort in Japan from 2020 to 2024. The clinical outcomes of 12 patients treated with the 7-on/7-off regimen and 23 patients treated with daily dosing were compared. There were significant differences in overall survival (12.4 months vs. 6.3 months, p = 0.03), median progression-free survival (4.8 months vs. 3.2 months, p < 0.01), objective response rate (16.7% vs. 0.0%, p = 0.04), and incidence of any adverse events (75.0% vs. 100.0%, p = 0.03) between the 7-on/7-off regimen group and daily dosing group. The median duration of drug exposure (122 days vs. 42 days, p < 0.01) and median duration of dose reduction (100 days vs. 23 days, p < 0.01) were prolonged significantly in the 7-on/7-off group than in the daily dosing group. CAB in a 7-on/7-off regimen may improve the tolerability and treatment response in patients with u-HCC.

Background/Objectives: Sustained drug-free status is an emerging milestone after atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. We examined baseline host biomarkers associated with achievement of 6-month sustained drug-free status and evaluated a composite stratification score. Methods: This multicentre retrospective study included patients treated with atezolizumab plus bevacizumab. The endpoint required systemic therapy discontinuation after complete response or no viable disease, followed by at least 6 months without viable or recurrent hepatocellular carcinoma and sustained normalization of initially elevated tumour markers. The PAN-DF score (preserved hepatic reserve, altered immune-inflammatory status, and nutritional-immune reserve for achieving drug-free status) combined modified albumin–bilirubin grade, neutrophil-to-lymphocyte ratio, and prognostic nutritional index. Results: Among 655 patients, 25 achieved the endpoint; median post-discontinuation follow-up was 533 days. In the complete-case cohort (n = 473; 17 events), achievement rates were 0.0%, 2.9%, 3.7%, and 13.6% for scores 0–3. Each one-point increase was associated with higher odds of achievement (odds ratio 2.90, 95% confidence interval 1.51–5.55; p = 0.001), and the area under the curve was 0.719. The examined baseline tumour-related factors were not significantly associated with the primary endpoint, and the examined host-related factors were not associated with objective response. Conclusions: Selected baseline host biomarkers were associated with achievement of 6-month sustained drug-free status. PAN-DF stratified the observed probability of this outcome and may help identify patient groups with a relatively higher likelihood of a sustained drug-free state, supporting early multidisciplinary planning.