Sorafenib plus hepatic arterial infusion chemotherapy versus sorafenib plus transarterial chemoembolization in advanced hepatocellular carcinoma: An update on SHATA-001 study.

Abstract

4100 Background: Although sorafenib plus transcatheter arterial chemoembolization (SoraTACE) has been widely applied for advanced hepatocellular carcinoma (HCC) in most Asian countries, sorafenib plus hepatic arteria infusion chemotherapy (SoraHAIC) may be a better alternative. Herein, we compared the efficacy and safety between the two groups in advanced HCC. Additionally, we validated a predictive model from our previous phase III trial (NCT02973685, cohort1). Methods: This phase III trial (NCT02856126) recruited participants with advanced HCC. Eligible participants were randomly assigned (2:1) to receive Sorafenib (400mg orally twice daily) plus HAIC per 3 weeks or TACE until disease progression or unacceptable toxicity. The Primary endpoint was overall survival (OS). Whole-exome sequencing (WES), RNA sequencing, and DNA methylation analysis of tumor biopsy samples were performed for predictive biomarker exploration (cohort 1) and validation (SHATA-001). Results: From August 2016 to October 2020, a total of 207 participants were allocated to receive SoraHAIC (n = 141) or SoraTACE (n = 66). The trial met the prespecified endpoints. SoraHAIC significantly prolonged OS compared to SoraTACE (median OS, 15.7 versus 11.2 months; p < 0.001). In the SoraTACE group, 56.7% of participants experienced grade 3 or 4 treatment-related adverse events, which were significantly higher than the SoraHAIC group (39.3%; p < 0.023). Severe adverse events were also more frequent in SoraTACE (15.7% vs 26.7%, p = 0.07). WES analysis found no ideal indicator in the mutational landscape for treatment outcome. We identified 1226 and 506 differentially methylated probes (DMPs) among the non-responsive specimens in the HAIC and TACE groups. Then we performed RNA-seq analysis. By comparing the transcriptome between the responsive and non-responsive groups, 685 and 600 differentially expressed genes (DEGs) were generated in the two treatment groups, respectively. In the HAIC group, pathways including leukocyte-mediated immunity and immune response-activating signaling pathway were enriched in the responders, while metabolic-related pathways including steroid metabolic process and alcohol biosynthetic process were enriched in the non-responders in the TACE group. Integrative analysis of DEGs and DMPs indicated phosphofructokinase (PFKM) could potentially stratify patients to HAIC or TACE as higher expression of PFKM was associated with favorable outcomes accepting TACE. Such performance could also be validated in this study as participants with elevated PFKM tended to benefit from SoraTACE. Conclusions: This trial demonstrated SoraHAIC significantly improved OS over SoraTACE in participants with advanced HCC. Participants with high PFKM expression benefited more from TACE. Clinical trial information: NCT02856126 .