1012P - First-in-human study of ABSK-011, a novel, highly selective fibroblast growth factor receptor (FGFR) 4 inhibitor for treating advanced hepatocellular carcinoma (HCC) with FGF19 overexpression

Background

FGF19 overexpression (+) is in ∼ 30% of HCC with poor prognosis, and studies suggested FGF19/FGFR4 signaling axis could be a therapeutic target for HCC. ABSK-011 is an oral, highly selective, and potent FGFR4 inhibitor for treating FGF19+ HCC.

Methods

The ongoing phase I study (NCT04906434) is to evaluate the safety, PK, PD, and preliminary efficacy of ABSK-011. ABSK-011 was given QD or BID orally in 28-day cycles.

Results

As of 30 JUN 2023, 75 patients (pts) were dosed with ABSK-011 ranging from 60 mg to 400 mg QD (N=48), and 160 mg to 220 mg BID (N=27); median age 53.0 y, 82.7% male, 69.3% ECOG PS 1. 72 pts were HCC, 95.8% with prior therapies, 79.2% FGF19+. 160 mg BID and 220 mg BID were selected as recommended doses of expansion (RDE) and all BID pts were FGF19+. Dose-limiting toxicities were observed in 2 pts (both 400 mg QD): diarrhea, ALT increased (↑), AST↑ and hyperbilirubinemia in 1 pt, hypokalemia in 1 pt. Most common treatment-related adverse events (TRAE) (any grade/≥G3) were diarrhea (72.0%/5.3%), ALT↑ (70.7%/10.7%), AST↑ (57.3%/9.3%), hyperphosphataemia (41.3%/0), blood bilirubin↑ (30.7%/1.3%), total bile acids↑ (21.3%/0). G3/4 TRAEs occurred in 29.3% of all pts (14.8% in BID ). No G5 TRAE. One complete response (CR) and 12 partial responses were reported by investigator assessment per RECIST 1.1 (including unconfirmed) among the 65 evaluable HCC pts with prior therapies. Longest duration of response (DoR) was 13.1 m and mDoR is not yet mature, with majority of responses ongoing. BID dosing showed encouraging efficacy with an overall response rate (ORR) of 43.5% (10/23, 1 CR), including 6 responders in 160 mg BID (6/18, 33.3%) and 4 in 220 mg BID (4/5, 80.0%). ABSK-011 demonstrated a favorable PK property approximately linear and time-invariant with higher C_trough and lower C_max at BID vs QD with comparable total daily dose. Pathway inhibition was observed by increased C4, total bile acids, FGF19, and decreased total cholesterol at all dose levels.

Conclusions

The promising response rate and manageable safety profile from this phase I study suggest that ABSK-011 may have clinical benefit for HCC pts with prior therapies through biomarker selection of FGF19.

Clinical trial identification

NCT04906434.

Editorial acknowledgement

Abbisko Therapeutics Co., Ltd.

Legal entity responsible for the study

Abbisko Therapeutics Co., Ltd.

Funding

Abbisko Therapeutics Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.