REG improved overall survival (OS) and time to progression (TTP) versus placebo in patients with HCC who progressed during prior sorafenib in the phase 3 RESORCE trial (Bruix et al, Lancet 2017). This exploratory analysis evaluated the potential of circulating miRNA plasma biomarkers to predict the OS and TTP benefit with REG in RESORCE.
Valid biomarker data were available for 343/573 patients. Expression levels of 750 plasma miRNAs collected at baseline were quantified by qPCR. To be eligible, miRNAs had to be measurable on a continuous scale or dichotomized by pre-processing (present vs absent), and present in ≥ 5% of patients (i.e. n ≥ 18). The predictive and prognostic effects (HR and 95% CI) were evaluated using a Cox proportional hazards model with miRNAs as continuous or dichotomized variables. A predictive effect was modeled as an miRNA–treatment interaction effect and subjected to Akaike information criterion (AIC)-based selection to assess its association with OS and TTP.
Demographic covariates were generally similar in the overall RESORCE and miRNA biomarker cohorts, except the latter had a smaller proportion of Asian patients. Of the 750 miRNAs analyzed, 25 showed a multiplicity-adjusted prognostic effect (P ≤ 0.05) for OS. Nine miRNAs showed a multiplicity-adjusted predictive effect (P ≤ 0.05) for OS; 3 of the 9 predictive markers were also prognostic (Table). No miRNA was found to be predictive for TTP.Table:
|miRNA||miRNA predictive for OS||miRNA prognostic for OS|
|HR (95% CI)||P-value||P-value|
|hsa-miR-15b-3p||0.37 (0.20, 0.70)||≤0.05||0.01|
|hsa-miR-107||0.54 (0.37, 0.81)||≤0.05||0.06|
|hsa-miR-320b||0.57 (0.41, 0.81)||≤0.05||0.01|
|hsa-miR-122-5p||1.35 (1.14, 1.60)||≤0.05||0.39|
|hsa-miR-374b-3p||1.36 (1.11, 1.65)||≤0.05||0.06|
|hsa-miR-200a-3p||1.39 (1.15, 1.68)||≤0.05||0.03|
|hsa-miR-30a-5p||1.47 (1.14, 1.88)||≤0.05||0.34|
|hsa-miR-125b-5p||1.54 (1.19, 1.99)||≤0.05||0.32|
|hsa-miR-645||3.16 (1.52, 6.55)||≤0.05||0.06|
This exploratory analysis suggests that multiple miRNAs may be potentially predictive for OS in patients treated with REG. The biological role of the miRNAs in HCC as well as their potential functional correlation to treatment benefit needs to be analyzed further.
Clinical trial identification
Legal entity responsible for the study
M. Teufel, G. Meinhardt: Stocks and Employment: Bayer. H. Seidel, K. Köchert: Employment: Bayer. R.S. Finn: Consulting and Advisory Role: Bayer, Pfizer, Novartis, BMS, Eisai. J.M. Llovet: Research/Education Grant: Bayer, Blueprint Medicines, BI, Incyte Advisory Board: Bayer, Eisai, BMS, Eli Lilly Consulting: Eli Lilly, Bayer, BMS, Blueprint Medicines, Eisai, Celsion, BI. J. Bruix: Research/Education Grant: Daiichi Sankyo, ArQule, Bayer, Sirtex. Honoraria: Gilead, AbbVie, Kowa, Bayer, BTG, ArQule, Terumo, Sirtex, BMS, Eisai, BI, Novartis, OSI, Roche, Onxeo. Advisory Board: Bayer, Kowa, BTG, ArQule, Terumo, Sirtex, BMS, Eisai, Novartis, OSI, Roche, Onxeo. Consulting: Gilead, AbbVie, Kowa, Bayer, BTG, ArQule, Terumo, Sirtex, BMS, BI, Kowa, Novartis, OSI, Roche, Onxeo, Daiichi Sankyo, Abbot, Glaxo, Eli Lilly.