A randomized, double-blinded, phase III study of icaritin versus huachashu as the first-line therapy in biomarker-enriched HBV-related advanced hepatocellular carcinoma with poor conditions: Interim analysis result.

4077 Background: Many advanced hepatocellular carcinoma (aHCC) patients (pts) are often with more complicated clinical conditions such as damaged liver or blood function, poor physical conditions. Those aHCC pts are not suitable for molecular target drug like sorafenib or systemic chemotherapy and no standard or generally accepted treatment. Icaritin, a single molecule ( > 98% purity) derived from Epimedii herba (Traditional Chinese herbal medicine), is a novel immune-modulation anti-tumor agent. Preclinical studies demonstrated that Icaritin induced anti-HCC activities through targeting IL-6/JAK//STAT3 pathways and modulating inflammation-immune systems including Th1 cytokines, and down-regulation of alpha-fetoprotein (AFP). Prior phase II study demonstrated favorable overall survival (OS) improvement in aHCC pts with poor conditions and correlated with the combined serum biomarkers. The current phase III study was designed to confirm above clinical benefits and safety of Icaritin in those patients. Methods: An adaptive enrichment design was used in a multicenter randomized, double-blinded study of comparing Icaritin with Huachashu (a TCM formula commonly used in China) as first line therapy for those aHCC pts (NCT03236636). The primary endpoint was overall survival (OS) and secondary endpoints included time-to-progression (TTP), progression-free-survival (PFS), disease control rate (DCR), and safety. The pts were randomized (1:1) to receive either Icaritin at 600mg or Huachashu. Based on prior studies, a composite biomarker score (CBS) of AFP(≥400 ng/mL), TNF-a( < 2.5 pg/mL) and IFN-g(≥7.0 pg/mL) was used for pts selection and a CBS score of 2/3 was predefined positive. Patients with CBS-positive were applied in interim analysis according to the protocol and statistical analysis plan (SAP). Results: A total of 283 aHCC pts were enrolled and randomized from Sept. 2017, and 71 enriched pts was CBS-positive with combined risk/poor prognosis factors such as BCLC stage C, HBV infection, and thrombocytopenia etc.. Thirty-three and 38 CBS-positive aHCC pts were treated with Icaritin or Huachashu, respectively. With a median follow-up of 8.1 mo (cutoff date, Dec.30,2020), the treatment outcomes for Icaritin and Huachashu arm showed following, that is mOS, 13.54 vs. 7.06 mo (HR = 0.40, 95%CI 0.21-0.77, p = 0.0046), mTTP, 3.65 vs. 1.84 mo (HR = 0.67, 95%CI, 0.36-1.22), mPFS, 2.79 vs. 1.84 mo (HR = 0.75, 95%CI, 0.43-1.33), and DCR, 48.5% vs. 26.3, respectively. Treatment-related adverse event (AE≥3 grades) observed were 15.2% vs. 31.6%, respectively. Conclusions: Small molecule immunomodulation agent Icaritin could significantly improve the overall survival with favorable safety in a prospectively CBS-enriched HBV-related advanced HCC pts with poor conditions. Clinical trial information: NCT03236636.