Division of Hematology and Medical Oncology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
Department of Internal Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.
Expert Opin Investig Drugs. 2021 Apr;30(4):309-316. doi: 10.1080/13543784.2021.1864320. Epub 2021 Jan 4.
The fibroblast growth factor receptor (FGFR) pathway is essential in cell proliferation, differentiation, migration, and survival. Cancers such as intrahepatic cholangiocarcinoma (IHCA) have demonstrated alterations of FGFR allowing unregulated growth. Infigratinib (BGJ398) is a potent ATP-competitive inhibitor of all four FGFR receptors as demonstrated by the consistently high prevalence of hyperphosphatemia, indicating disruption of FGFR-related phosphate homeostasis.
In this article, the authors discuss preclinical studies and the biological characterization of BGJ398 that inspired its investigation for cancer treatment. They summarize results from phase I and II studies and comment on ongoing phase III clinical trials primarily focusing on its role in treating IHCA.
Infigratinib exhibits high potency FGFR1-3 inhibition in preclinical studies. Clinically, agents targeting FGFR including infigratinib show promising anti-tumor activity in targeted trials. Pemigatinib, an FGFR inhibitor, has recently been approved by the FDA for use in refractory IHCA. We believe infigratinib represents a promising agent in the treatment of refractory IHCA with FGFR2 fusions and is uniquely positioned to be a potential option in chemonaive patient populations. An ongoing phase III trial (PROOF-301) compares the efficacy and safety of infigratinib versus standard gemcitabine and cisplatin in untreated patients with IHCA and FGFR2 fusions.
成纤维细胞生长因子受体（FGFR）通路在细胞增殖、分化、迁移和存活中至关重要。肝内胆管癌（IHCA）等癌症表现出 FGFR 的改变，允许不受调节的生长。英菲格拉替尼（BGJ398）是一种有效的、与 ATP 竞争的所有四种 FGFR 受体抑制剂，这一点从高磷酸血症的高发生率中得到了一致的证明，表明 FGFR 相关的磷酸盐内稳态受到了破坏。
本文作者讨论了 BGJ398 的临床前研究和生物学特征，这些研究激发了对其癌症治疗的研究。他们总结了 I 期和 II 期研究的结果，并对正在进行的 III 期临床试验进行了评论，主要关注其在治疗 IHCA 中的作用。
英菲格拉替尼在临床前研究中表现出对 FGFR1-3 的高抑制活性。在临床上，靶向 FGFR 的药物，包括英菲格拉替尼，在靶向试验中显示出有希望的抗肿瘤活性。FGFR 抑制剂培米替尼最近已被 FDA 批准用于治疗难治性 IHCA。我们认为英菲格拉替尼是治疗 FGFR2 融合难治性 IHCA 的一种很有前途的药物，并且在化疗初治患者中具有独特的地位，可能成为一种潜在的选择。一项正在进行的 III 期试验（PROOF-301）比较了英菲格拉替尼与标准吉西他滨和顺铂在未经治疗的伴有 FGFR2 融合的 IHCA 患者中的疗效和安全性。
