Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY, 10065, USA.
Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA.
Target Oncol. 2023 Mar;18(2):181-193. doi: 10.1007/s11523-023-00948-8. Epub 2023 Feb 14.
Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models.
This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination.
Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations < 40.9 ng/mL and concomitant prophylactic bile acid sequestrant treatment. No additional DLTs were reported at 10 and 15 mg twice daily; higher doses were not assessed. The most common toxicity was diarrhea (60.9%). INCB062079 exposure was dose-proportional; FGF19 and bile acid/C4 concentrations increased with exposure. One partial response was achieved (15 mg twice daily; ovarian cancer; FGF/FGFR status unknown; duration of response, 7.5 months); two patients had stable disease.
With C4 cut-off and prophylactic bile acid sequestrant implementation, INCB062079 demonstrated a manageable safety profile and evidence of target inhibition. In view of the rarity of FGF19/FGFR4 alterations and slow patient accrual, the study was terminated before establishing an MTD.
成纤维细胞生长因子受体（FGFR）-4/FGF19 通路失调与肝胆和其他实体瘤有关。INCB062079 是一种口服、选择性 FGFR4 抑制剂，可抑制 FGF19/FGFR4 驱动的肝癌模型的生长。
这是一项两部分、I 期研究（NCT03144661），纳入既往接受治疗的晚期实体瘤患者。主要目的是确定安全性、耐受性和最大耐受剂量（MTD），次要目的包括药代动力学、药效学（血浆 FGF19；胆汁酸盐/7α-羟基-4-胆甾烷-3-酮[C4]水平）和初步疗效。在第 1 部分中，患者接受 INCB062079 治疗，起始剂量为每日 10 mg，采用 3+3 剂量递增。由于研究终止，第 2 部分（剂量扩展）未进行。
共治疗 23 例患者（肝胆肿瘤，n=11；卵巢肿瘤，n=9；其他肿瘤，n=3）。在接受每日 2 次 15 mg 治疗的 6 例患者中，有 2 例出现剂量限制性毒性（DLT；3 级腹泻，3 级转氨血症）。这 2 例患者均有较高的预处理 C4 浓度，促使修订方案要求预处理 C4 浓度＜40.9ng/mL 并同时进行预防性胆汁酸螯合剂治疗。每日 2 次 10 和 15 mg 治疗时未报告其他 DLT；未评估更高剂量。最常见的毒性是腹泻（60.9%）。INCB062079 暴露与剂量呈比例关系；FGF19 和胆汁酸/C4 浓度随暴露量增加而增加。1 例患者（每日 2 次 15 mg，卵巢癌；FGF/FGFR 状态未知；缓解持续时间 7.5 个月）获得部分缓解，2 例患者疾病稳定。
采用 C4 截断值和预防性胆汁酸螯合剂后，INCB062079 显示出可管理的安全性特征和靶标抑制证据。鉴于 FGF19/FGFR4 改变的罕见性和患者入组缓慢，在确定 MTD 之前，该研究提前终止。
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