Yu James, Mahipal Amit, Kim Richard
Department of Internal Medicine, Adventhealth Orlando, Orlando, FL, USA.
Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Onco Targets Ther. 2021 Oct 23;14:5145-5160. doi: 10.2147/OTT.S272208. eCollection 2021.
Cholangiocarcinoma is one of the most aggressive cancers, with a 5-year survival rate of 11-44% after surgical resection. However, there is no established systemic therapy after failure of the gemcitabine plus cisplatin first-line therapy with exception of FOLFOX. Fibroblast growth factor receptor (FGFR) genomic aberrations have been detected in cholangiocarcinoma, and targeting these genomic aberrations with FGFR inhibitors has shown remarkable clinical benefits in advanced cholangiocarcinoma. In this article, we provide up-to-date information on the clinical development of selective FGFR inhibitors in advanced cholangiocarcinoma, focusing on infigratinib. In a Phase 1 trial, infigratinib showed a safe profile. In a following Phase 2 trial, infigratinib showed remarkable efficacy in advanced cholangiocarcinoma with FGFR2 fusions or rearrangements, and the Food and Drug Administration (FDA) approved infigratinib for cholangiocarcinoma in May 2021 largely based on tumor response and duration of response. Currently infigratinib is on a Phase 3 trial (PROOF301) as a first-line setting compared to the GEMCIS therapy in advanced cholangiocarcinoma. Given that the FGFR genomic aberrations including FGFR2 fusions are rarely accompanied with other targetable mutations, infigratinib and other FGFR inhibitors are continuously expected to be the novel targeted agents in cholangiocarcinoma harboring these aberrations. Acquired resistance to infigratinib was reported in several recent studies which could potentially be a barrier to overcome. Active clinical trials including PROOF301 are expected to elucidate the clinical benefits of infigratinib in this disease. Infigratinib combined with immunotherapy is also a potential future direction of investigation in cholangiocarcinoma.
胆管癌是侵袭性最强的癌症之一，手术切除后的5年生存率为11%-44%。然而，除FOLFOX方案外，吉西他滨联合顺铂一线治疗失败后尚无既定的全身治疗方案。在胆管癌中已检测到成纤维细胞生长因子受体（FGFR）基因组畸变，用FGFR抑制剂靶向这些基因组畸变已在晚期胆管癌中显示出显著的临床益处。在本文中，我们提供了关于选择性FGFR抑制剂在晚期胆管癌临床开发的最新信息，重点介绍了英菲格拉替尼。在一项1期试验中，英菲格拉替尼显示出安全性良好。在随后的2期试验中，英菲格拉替尼在伴有FGFR2融合或重排的晚期胆管癌中显示出显著疗效，美国食品药品监督管理局（FDA）于2021年5月批准英菲格拉替尼用于胆管癌，这主要基于肿瘤反应和反应持续时间。目前，英菲格拉替尼正在进行3期试验（PROOF301），作为晚期胆管癌一线治疗方案与GEMCIS疗法进行比较。鉴于包括FGFR2融合在内的FGFR基因组畸变很少伴有其他可靶向突变，英菲格拉替尼和其他FGFR抑制剂有望持续成为携带这些畸变的胆管癌的新型靶向药物。最近的几项研究报道了对英菲格拉替尼的获得性耐药，这可能是一个需要克服的障碍。包括PROOF301在内的正在进行的临床试验有望阐明英菲格拉替尼在这种疾病中的临床益处。英菲格拉替尼联合免疫疗法也是胆管癌未来潜在的研究方向。
