# Safety and efficacy of PD-1 inhibitors plus tyrosine kinase inhibitors combination therapy in patients with advanced hepatocellular carcinoma combined with hyperbilirubinemia: a retrospective cohort study

## TL;DR

This study examines the safety and effectiveness of combining PD-1 inhibitors and tyrosine kinase inhibitors in treating advanced liver cancer patients with high bilirubin levels.

## Contribution

The study is the first to evaluate PD-1 inhibitor plus TKI therapy in HCC patients with hyperbilirubinemia, showing it can be safe and effective.

## Key findings

- Combination therapy showed acceptable safety with most adverse events being mild.
- Patients with reduced bilirubin levels early in treatment had significantly better survival outcomes.
- MELD score >18 and rising bilirubin were risk factors for poor survival.

## Abstract

Programmed death-1 (PD-1) inhibitors plus tyrosine kinase inhibitors (TKIs) combination therapy are considered as a first-line treatment recommendation for advanced hepatocellular carcinoma (HCC). However, patients with hyperbilirubinemia are excluded from this therapeutic option due to limitations in indications. There is a notable absence of published studies evaluating the safety and efficacy of the PD-1 inhibitors plus TKIs combination therapy in patients with HCC combined with hyperbilirubinemia.

Patients with HCC complicated with hyperbilirubinemia who received combination therapy with PD-1 inhibitors and TKIs were retrospectively analyzed. Adverse events, tumor response, and laboratory parameters were recorded to assess the safety and efficacy of the treatment, as well as to identify potential risk factors influencing survival.

A total of 108 participants were included in the study, with 56 patients (51.9%) reporting at least one adverse event, the majority of which were mild. The objective response rate (ORR) for the enrolled participants was 11.9%, and the disease control rate(DCR) reached 61.2%. The median overall survival (OS) for the entire cohort was 5.03 months, while the median progression-free survival (PFS) was 3.63 months. Multifactorial analysis showed that MELD score >18 and increased total bilirubin (TBIL) levels within one week were significant risk factors for OS. Patients with a decrease in TBIL levels within one week had significantly prolonged median OS (not reached vs 3.3months, P =0.013) and median PFS (7.03 months vs 2.77 months, P =0.010).

Combination therapy demonstrated favorable safety and tolerability among patients with HCC combined with hyperbilirubinemia. Patients who experienced a rapid decline in TBIL levels during the early phase of treatment with PD-1 inhibitors and TKIs were observed to derive clinical benefits. Early initiation of aggressive interventions aimed at reducing TBIL levels is recommended to optimize treatment outcomes.