FGF401 单药及联合 Spartalizumab 在肝细胞癌或生物标志物选择的实体瘤患者中的首次人体 1/2 期研究。
A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors.
机构信息
State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China.
West German Cancer Center, University Hospital Essen, Germany & German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany.
出版信息
J Exp Clin Cancer Res. 2022 Jun 2;41(1):189. doi: 10.1186/s13046-022-02383-5.
BACKGROUND
Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab.
METHODS
Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC.
RESULTS
Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR.
CONCLUSIONS
At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted.
TRIAL REGISTRATION
NCT02325739 .
背景
成纤维细胞生长因子 19-成纤维细胞生长因子受体 4 信号的失调存在于多种癌症中，包括肝细胞癌（HCC），使其成为治疗靶点。FGF401 是一种有效的、选择性的 FGFR4 抑制剂，在临床前模型中具有抗肿瘤活性。本研究旨在确定推荐的 2 期剂量（RP2D），描述 PK/PD 特征，并评估 FGF401 单药治疗以及与抗 PD-1 抗体 Spartalizumab 联合治疗的安全性和疗效。
方法
招募患有 HCC 或其他表达 FGFR4/klb 的肿瘤的患者。剂量递增由贝叶斯模型指导。2 期剂量扩展招募了来自亚洲国家（第 1 组）、非亚洲国家（第 2 组）的 HCC 患者和表达 FGFR4 和 KLB 的其他实体瘤患者（第 3 组）。在 HCC 患者中评估了 FGF401 和 Spartalizumab 联合治疗。
结果
74 例患者在 I 期接受了 50 至 150mg 的单药 FGF401 治疗。FGF401 表现出良好的 PK 特征，并且当与低脂肪餐一起给药时没有食物效应。确定 120mg qd 为 RP2D。70 例患者中有 6 例发生 3 级剂量限制性毒性：转氨酶升高（n=4）或血胆红素升高（n=2）。在 2 期，第 1 组 30 例，第 2 组 36 例，第 3 组 20 例患者接受了 FGF401 治疗。共有 8 例患者出现客观缓解（1 例 CR，7 例 PR；分别在 I 期和 2 期各有 4 例）。常见的不良反应（AE）为腹泻（73.8%）、AST 升高（47.5%）和 ALT 升高（43.8%）。C4、总胆汁酸和循环 FGF19 水平的升高证实了有效的 FGFR4 抑制。12 例患者接受了 FGF401 联合 Spartalizumab 治疗。确定了 FGF401 120mg qd 和 Spartalizumab 300mg Q3W 的 RP2D；2 例患者报告了 PR。
结论
在具有生物活性的剂量下，FGF401 单药或与 Spartalizumab 联合治疗 FGFR4/klb 阳性肿瘤，包括 HCC，是安全的。观察到初步的临床疗效。需要进一步的临床评估，使用更精细的生物标志物策略来评估 FGF401。
试验注册
NCT02325739。
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