Concurrent loco-regional therapy associated with improved survival in non-virus-related unresectable hepatocellular carcinoma who received systemic therapies: a multi-center retrospective cohort study (CLEAP-2502)

Background: Non‑virus-related hepatocellular carcinoma (HCC) is usually driven by metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease, are often diagnosed at an advanced tumor stage and presenting poor response towards therapies. Although adding loco-regional therapies (LRT) to systemic regimens improves outcomes in hepatitis B virus (HBV)‑predominant cohorts, evidence is limited in non‑virus-related HCC. We evaluated the value of concurrent LRT to improve prognosis in non‑virus-related unresectable HCC (uHCC) who received systemic therapy.

Methods: We conducted a multi‑center, retrospective cohort study of first‑line systemic therapies with or without concurrent LRT in non‑virus-related uHCC. Primary endpoint was overall survival (OS); secondary endpoints included progression‑free survival (PFS), post‑progression survival (PPS), objective response rate (ORR), and grade ≥3 treatment‑related adverse events. Analyses used Kaplan-Meier, multivariable Cox models, and propensity methods (PSM/IPTW) to adjust for confounding. Exploratory comparisons of the findings were made to a virus-related uHCC cohort who received analogous therapies from the CLEAP-001 study.

Results: Among 95 non‑virus-related uHCC patients (median age 62; predominantly Child-Pugh A), concurrent LRT with systemic therapy were significantly associated with improved OS versus systemic therapy alone [hazard ratio (HR), 0.190; 95% confidence interval (95% CI), 0.040 to 0.450; P=0.007], with consistent benefits after PSM and IPTW. PPS was also prolonged with combination therapy, whereas PFS and ORR were similar between groups. Safety profiles were comparable, with no increase in serious adverse events and no treatment‑related deaths. In exploratory analyses, patients with non‑virus-related HCC receiving concurrent LRT demonstrated extra benefit in OS and PPS compared with virus-related uHCC who received similar treatments.

Conclusions: In non‑virus-related uHCC, integrating LRT were associated with significantly improved OS and PPS with acceptable safety profile. These findings support combining LRT with systemic regimens for non‑virus-related uHCC patients with compensatory liver function.