# Itacitinib in advanced hepatocellular cancer following first line therapy

## TL;DR

This study tests itacitinib, a JAK1 inhibitor, as a treatment for advanced liver cancer after first-line therapies fail.

## Contribution

The study introduces itacitinib as a potential second- or third-line therapy targeting liver inflammation in hepatocellular carcinoma.

## Key findings

- Itacitinib showed stable disease in 47% of patients with advanced hepatocellular carcinoma.
- Median progression-free survival was 3.5 months and median overall survival was 7.4 months.
- A transcriptomic signature predictive of response was identified in tumor and serum samples.

## Abstract

Hepatocellular carcinoma (HCC) develops on background chronic liver disease where uncontrolled inflammation drives hepatocarcinogenesis. First-line therapies have limited response. There are no agents that specifically target the underlying liver inflammation. We investigated the safety and efficacy of itacitinib, a highly selective JAK1 inhibitor, as a potential second- or third-line therapy. Biomarkers of response were investigated. Participants with advanced stage HCC, Child Pugh ≤B7 who had progressed through at least one previous line of therapy received 400 mg of itacitinib QID every 28 days. Treatment-related adverse events (trAEs) were assessed weekly during cycle 1 then every 28 days (CTC-AE version 4.03). Response was assessed 8-weekly using RECIST 1.1. Progression-free (PFS) and overall survival (OS) were reported as secondary endpoints. Tumour samples were analysed for targeted transcriptomics. Sequential serum samples were assessed for metabonomic determinants of toxicity and response. 19 patients were enrolled. The most common trAEs were thrombocytopenia (31%), fatigue (26%) and palmar-plantar erythrodysesthesia syndrome (26%); four episodes of dose-limiting thrombocytopaenia were observed. Over a median follow-up of 3.5 months, the best overall response was stable disease (47%). Median PFS and OS were 3.5 (95% CI: 2.6 - 4.5 months) and 7.4 months (95% CI: 4.3-10.5 months), respectively. Subgroup analysis illustrated a significantly increased risk of progression for patients that had received combination immunotherapy prior to itacitinib (HR 4.7, 95%CI 1.3-16.6, p = 0.016). Untargeted tumour and serum transcriptomics identified a signature predictive of response. Itacitinib either as second- or third-line therapy showed promising activity. We identified a transcriptomic signature predictive of response.