TY - JOUR
T1 - First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma
T2 - Preliminary results of safety, durable survival and immune biomarkers
AU - Fan, Ying
AU - Li, Shu
AU - Ding, Xiaoyan
AU - Yue, Jian
AU - Jiang, Jun
AU - Zhao, Hong
AU - Hao, Rui
AU - Qiu, Weiliang
AU - Liu, Kezhen
AU - Li, Ying
AU - Wang, Shengdian
AU - Zheng, Limin
AU - Ye, Bin
AU - Meng, Kun
AU - Xu, Binghe
N1 - Publisher Copyright:
© 2019 The Author(s).
PY - 2019/3/28
Y1 - 2019/3/28
N2 - Background: With poor prognosis and limited treatment options for advanced hepatocellular carcinoma (HCC), development of novel therapeutic agents is urgently needed. This single-arm phase I study sought to assess the safety and preliminary efficacy of icaritin in human as a potential oral immunotherapy in addition to the immune-checkpoint inhibitors. Methods: Eligible advanced HCC patients with Child-Pugh Class A or B were administered with a fixed oral dose of icaritin at either 600 or 800 mg b.i.d. The primary endpoint was safety, and the secondary endpoints included time-to-progression (TTP), overall survival (OS) and the clinical benefit rate (CBR). Icaritin treatment induced immune biomarkers and immune-modulating activities in myeloid cells were also explored. Results: No drug-related adverse events ≥ Grade 3 were observed in all 20 enrolled HCC patients. Among the 15 evaluable patients, 7 (46.7%) achieved clinical benefit, representing one partial response (PR, 6.7%) and 6 stable disease (SD, 40%). The median TTP was 141 days (range: 20-343 days), and the median OS was 192 days (range: 33-1036 days). Durable survival was observed in PR/SD patients with a median OS of 488 days (range: 72-773). TTP was significantly associated with the dynamic changes of peripheral neutrophils (p = 0.0067) and lymphocytes (p = 0.0337). Icaritin treatment induced changes in immune biomarkers-and immune-suppressive myeloid cells were observed. Conclusions: Icaritin demonstrated safety profiles and preliminary durable survival benefits in advanced HCC patients, which were correlated with its immune-modulation activities and immune biomarkers. These results suggested the potential of icaritin as a novel oral immunotherapy for advanced HCC in addition to antibody-based PD-1/PD-L1 blockade therapies. Trial registration: Clinicaltrial.gov identifier. NCT02496949 (retrospectively registered, July 14, 2015).
AB - Background: With poor prognosis and limited treatment options for advanced hepatocellular carcinoma (HCC), development of novel therapeutic agents is urgently needed. This single-arm phase I study sought to assess the safety and preliminary efficacy of icaritin in human as a potential oral immunotherapy in addition to the immune-checkpoint inhibitors. Methods: Eligible advanced HCC patients with Child-Pugh Class A or B were administered with a fixed oral dose of icaritin at either 600 or 800 mg b.i.d. The primary endpoint was safety, and the secondary endpoints included time-to-progression (TTP), overall survival (OS) and the clinical benefit rate (CBR). Icaritin treatment induced immune biomarkers and immune-modulating activities in myeloid cells were also explored. Results: No drug-related adverse events ≥ Grade 3 were observed in all 20 enrolled HCC patients. Among the 15 evaluable patients, 7 (46.7%) achieved clinical benefit, representing one partial response (PR, 6.7%) and 6 stable disease (SD, 40%). The median TTP was 141 days (range: 20-343 days), and the median OS was 192 days (range: 33-1036 days). Durable survival was observed in PR/SD patients with a median OS of 488 days (range: 72-773). TTP was significantly associated with the dynamic changes of peripheral neutrophils (p = 0.0067) and lymphocytes (p = 0.0337). Icaritin treatment induced changes in immune biomarkers-and immune-suppressive myeloid cells were observed. Conclusions: Icaritin demonstrated safety profiles and preliminary durable survival benefits in advanced HCC patients, which were correlated with its immune-modulation activities and immune biomarkers. These results suggested the potential of icaritin as a novel oral immunotherapy for advanced HCC in addition to antibody-based PD-1/PD-L1 blockade therapies. Trial registration: Clinicaltrial.gov identifier. NCT02496949 (retrospectively registered, July 14, 2015).
KW - Phase I trial in advanced hepatocellular carcinoma
KW - Small molecule immune modulation
UR - https://www.scopus.com/pages/publications/85063746188
U2 - 10.1186/s12885-019-5471-1
DO - 10.1186/s12885-019-5471-1
M3 - 文章
C2 - 30922248
AN - SCOPUS:85063746188
SN - 1471-2407
VL - 19
JO - BMC Cancer
JF - BMC Cancer
IS - 1
M1 - 279
ER -
