Icaritin, a Novel Small-Molecule Immune Modulator in HBV-Related Refractory Advanced Hepatocellular Carcinoma: Safety, Immune Response, Durable Survival and Potential Predictive Biomarkers

Abstract

Background: Despite the fact that approved kinase inhibitors and immune checkpoint inhibitors (ICIs) have improved overall survival (OS), a significant number of advanced hepatocellular carcinoma (HCC) patients have limited treatment options, particularly in developing countries. This phase II study aimed to explore the clinical efficacy of icaritin, a novel anti-inflammatory immune-modulatory small molecule, as potential oral administrative immunotherapy in HBV-related refractory advanced HCC patients. Methods: Major eligibility criteria included histologically confirmed unresectable advanced HCC with Child-Pugh class A or B liver function. Clinical endpoints included clinical efficacy and safety. Exploratory endpoints included immune biomarkers. Kaplan-Meier analysis was performed to correlate the immune response with OS and the associated biomarkers. Findings: No drug-related adverse events (AEs)≥grade III were observed in the enrolled cohort of 68 advanced HCC patients, 19 (28%) of whom were Child-Pugh class B and 62 (91.1%) of whom were hepatitis B virus positive(HBV+). The objective response evaluation showed cases of a partial response (PR) (1.7%), stable disease (SD) (32.8%) and progressive disease (PD) (59.0%), with a median overall survival (mOS) 254 days (95% CI, 172-296). The disease control rate (DCR) was 35.6% (95% CI, 22.7-47.7). Changes in the biomarkers IL-6, IL-8, IL-10, TNF-I±, TIM3, and LAG3 were significantly associated with OS. The mOS rates for the subgroups of HCC patients based on PD-L1 and IL-8 were 469 days (95%CI, 284-NA) and 475.5 days (95%CI, 309-NA), respectively. Whole-genome sequencing (WGS) analysis revealed that patients with high neoantigen levels or S. maltophilia positive showed a significant improvement in mOS. Interpretation: Icaritin demonstrated favorable clinical safety, an immune response based on a biomarker panel and associated with a significant improvement in durable survival. The potential biomarkers PD-L1, IL-8, neoantigen and S. maltophilia may predict the efficacy of icaritin treatment in HBV-related refractory advanced HCC patients. Clinical Trial Registration: Clinicaltrial.gov identifier: NCT01972672. Declaration of Interests: SQ, QL, J X, J L, Y C, J J, H Y7, HT; LZ, ZW; ZH, and YS declare no competing interests. SL is ex-employee and shareholder of Beijing Shenogen, BY, and KM are employees and shareholders of Beijing Shenogen Biomedical Ltd. Funding Statement: Beijing Shenogen Biomedical, Ltd. Ethical Approval Statement: All patients provided written informed consent before enrollment. The study was performed in accordance with good clinical practice and the Declaration of Helsinki guidelines. Approval from the appropriate ethics committees and institutional review boards was obtained and documented before the study. (Name of ethics committee: Cancer Hospital, Chinese Academy of Medical Sciences, National GCP Center for Anticancer Drugs; Ethic approval letter ID: 11-95/530, Clinical Protocol ID: TG11141CR; Approval date: Nov. 24, 2011).