Elevated IL-17A Level and Poor Prognosis in HCC Patients Receiving PD-1 Inhibitor Plus Targeted

07 Apr 20264 min read0 viewsJournal Feed

GIST

BackgroundCombination therapy with programmed death-1 (PD-1) inhibitors and targeted therapy is a first-line treatment for advanced hepatocellular carcinoma (HCC). Patients with hyperbilirubinemia (total bilirubin > upper limit of normal) are often excluded from such regimens.

This study aimed to evaluate the efficacy and safety of PD-1 inhibitor plus targeted therapy in this patient population and to identify plasma protein biomarkers associated with prognosis.MethodsWe enrolled 201 patients with advanced HCC who received PD-1 inhibitor plus targeted therapy. After propensity score matching (1:1), 60 pairs of patients with hyperbilirubinemia and normal bilirubin were compared in terms of objective response rate (ORR), disease control rate (DCR), and overall survival (OS).

Baseline plasma samples from 72 patients (28 with hyperbilirubinemia, 44 with normal bilirubin) were analyzed using Olink proteomics to quantify 92 inflammatory proteins. Differentially expressed proteins were identified, and the functional pathways were examined.

The prognostic value of key proteins was assessed using Cox regression and Kaplan-Meier survival analysis.ResultsThe combination therapy was well tolerated in the hyperbilirubinemia group, with no increase in severe hepatotoxicity. ORR (7.0% vs.

Clinical Editorial

Context and study scope

The investigation focused on advanced hepatocellular carcinoma patients receiving a combination of PD-1 inhibitors and targeted therapy as a first-line approach.
A specific subgroup with hyperbilirubinemia (total bilirubin above the upper limit of normal) was scrutinized due to frequent exclusion from such regimens.
The study sought both efficacy and safety signals, alongside the discovery of plasma protein biomarkers linked to prognosis.

Study design and population

The cohort comprised 201 advanced HCC patients treated with PD-1 blockade plus targeted agents.
After propensity score matching at a 1:1 ratio, 60 matched pairs were analyzed, comparing hyperbilirubinemia versus normal bilirubin groups across objective response rate (ORR), disease control rate (DCR), and overall survival (OS).
Baseline plasma for proteomic analysis was available from 72 patients (28 with hyperbilirubinemia; 44 with normal bilirubin).

Intervention and efficacy signals

The treatment regimen was characterized as well tolerated in the hyperbilirubinemia cohort, with no observed rise in severe hepatotoxicity compared to the normobilirubinemic group.
Efficacy differences emerged between bilirubin strata: ORR was lower in the hyperbilirubinemia group (7.0%) than in the normal bilirubin group (20.7%), with statistical significance (P = 0.043).
DCR followed a similar pattern, being reduced in hyperbilirubinemia patients (50.9%) versus those with normal bilirubin (72.4%; P = 0.022).
Median OS favored the normal bilirubin group, with hyperbilirubinemia associated with shorter survival (hazard ratio [HR] 0.54; 95% CI 0.35–0.84; P = 0.0065) in the overall comparison.

Biomarker discovery and prognostic implications

Proteomic profiling identified 36 proteins with differential expression between groups.
In univariate Cox regression within the hyperbilirubinemia subset, elevated plasma IL-17A correlated with poorer OS (HR 1.63; 95% CI 1.04–2.55; P = 0.033).
Stratifying by median IL-17A levels revealed that hyperbilirubinemia patients with high IL-17A had markedly worse OS (HR 2.89; 95% CI 1.03–8.07; P = 0.035).
In contrast, IL-17A levels did not significantly impact OS among patients with normal bilirubin (P = 0.870).
An interaction assessment demonstrated that the adverse effect of high IL-17A was amplified in the setting of hyperbilirubinemia (HR 2.72; 95% CI 1.28–5.75; P = 0.009).

Limitations and uncertainty

The report notes a limited sample for proteomic analyses and subgroup stratifications, which constrains precision and generalizability.
Although the combination therapy appears feasible in hyperbilirubinemia, its relative efficacy remains inferior to that observed in patients with normal bilirubin.