# Carry-over effect of immunotherapy in patients with advanced hepatocellular carcinoma

## TL;DR

This study shows that immunotherapy for advanced liver cancer can have lasting benefits even after treatment stops, improving survival in later treatments.

## Contribution

The study provides evidence for the carry-over effect of immunotherapy in advanced hepatocellular carcinoma, influencing post-progression and second-line survival.

## Key findings

- Patients with clinical benefit from first-line immunotherapy had significantly longer post-progression survival and second-line progression-free survival.
- Clinical benefit from first-line immunotherapy remained an independent predictor of improved survival outcomes in multivariate analysis.
- The carry-over effect was not observed in patients who received first-line multikinase inhibitors.

## Abstract

Combination immunotherapy is the current standard for treating advanced hepatocellular carcinoma (HCC). The response elicited by upfront immune checkpoint inhibitors (ICIs) might influence the efficacy of salvage therapy, a phenomenon known as the carry-over effect. This effect is thought to stem from immune memory and sustained immune activation, providing extended protection against tumor progression and resulting in a durable response even after discontinuation of ICI. This study aimed to investigate the carry-over effect of first-line ICI therapy in patients with advanced HCC.

Patients who received first-line ICI therapy for advanced HCC from December 2017 to December 2021 were included if they exhibited disease progression and received second-line systemic therapy. We analyzed the associations between clinical benefit (classified as complete, partial response and stable disease) of first-line ICI therapy, post-progression survival (PPS) and second-line progression-free survival (PFS). We used a historical cohort of patients receiving first-line multikinase inhibitor (MKI) for comparison.

A total of 137 patients were analyzed. We included 60 patients who received first-line ICI therapy, of which clinical benefit was detected in 46 (76.7%). Compared with patients without clinical benefit of first-line ICI therapy, patients with clinical benefit exhibited significantly longer PPS (median: 14.6 vs. 4.9 months, P = 0.024) and second-line PFS (median: 3.6 vs. 1.6 months, P = 0.027). In multivariate analysis, clinical benefit of first-line ICI therapy remained an independent predictor of PPS [hazard ratio (HR): 0.295, P = 0.005] and second-line PFS (HR: 0.484, P = 0.047). Conversely, clinical benefit was not associated with PPS among patients receiving first-line MKI therapy in both univariate and multivariate analysis in historical MKI cohort.

Clinical benefit of first-line ICI therapy was associated with PPS and second-line PFS in patients with advanced HCC, suggestive of the carry-over effect of ICI.

The online version contains supplementary material available at 10.1007/s00262-025-04052-w.