Clinical Oncology Unit, Careggi University Hospital, Florence, Italy.
Clinical Oncology Unit, Careggi University Hospital, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Pharmacol Ther. 2022 Sep;237:108170. doi: 10.1016/j.pharmthera.2022.108170. Epub 2022 Mar 13.
To date, treatment options for patients with chemorefractory cholangiocarcinoma (CCA) are limited. However, the advancements in molecular techniques have recently increased the opportunity to offer molecularly targeted therapies to patients with several cancer types and some targetable oncogenic alterations have been identified also in CCA. Among these potentially actionable molecular alterations, isocitrate dehydrogenase-1 (IDH1) mutations have been detected in approximately 10-20% of intrahepatic CCA (iCCA). IDH1 is responsible for the accumulation of oncometabolites inducing epigenetic changes that are involved in various signaling pathways. Ivosidenib is the first IDH1 inhibitor which significantly improved progression-free survival (PFS) (2.7 vs 1.4 months) and overall survival (OS) (10.3 vs 5.1 months [adjusted median OS]) compared with placebo in chemorefractory IDH1-mutated CCA. The very low incidence of grade (G) 3-4 adverse events (AEs) and treatment discontinuation due to toxicity, associated with a significantly less marked decline in health-related quality of life for patients in the ivosidenib group than in placebo group, facilitates patient adherence and clinician confidence. Here, we review the development of ivosidenib in CCA patients and evaluate the clinical impact of the results of the phase III ClarIDHy trial which was responsible for the Food and Drug Administration (FDA) approval for patients with IDH1-mutated CCA whose disease progressed after standard chemotherapy (CT). We also discuss the known primary and secondary resistance mechanisms, including concomitant and acquired mutations in other genes (e.g. IDH2 mutations), second-site mutation in IDH1, and enhanced activation of other pathways (e.g. PI3K/AKT/mTOR pathway). Finally we examine the future directions, as the opportunity to combine ivosidenib with other synergistic agents, including standard chemotherapy (CT), immune checkpoint inhibitors (ICIs), and IDH2 inhibitors.
迄今为止，化疗耐药性胆管癌 (CCA) 患者的治疗选择有限。然而，分子技术的进步最近为多种癌症类型的患者提供了分子靶向治疗的机会，并且在 CCA 中也确定了一些可靶向的致癌改变。在这些潜在的可操作分子改变中，异柠檬酸脱氢酶 1 (IDH1) 突变约在 10-20%的肝内 CCA (iCCA) 中被检测到。IDH1 负责积累致癌代谢物，诱导涉及各种信号通路的表观遗传改变。ivosidenib 是第一个 IDH1 抑制剂，与安慰剂相比，在化疗耐药性 IDH1 突变型 CCA 患者中显著改善了无进展生存期 (PFS) (2.7 个月比 1.4 个月) 和总生存期 (OS) (10.3 个月比 5.1 个月[调整后的中位 OS])。ivosidenib 组与安慰剂组相比，G3-4 级不良事件 (AE) 和因毒性而停药的发生率非常低，患者健康相关生活质量的下降明显较轻，这有助于提高患者的依从性和临床医生的信心。在这里，我们回顾了ivosidenib 在 CCA 患者中的开发情况，并评估了 III 期 ClarIDHy 试验的临床影响，该试验导致 FDA 批准了 IDH1 突变型 CCA 患者，这些患者在标准化疗 (CT) 后疾病进展。我们还讨论了已知的原发性和继发性耐药机制，包括其他基因 (如 IDH2 突变) 的伴随和获得性突变、IDH1 的第二部位突变，以及其他途径 (如 PI3K/AKT/mTOR 途径) 的增强激活。最后，我们研究了未来的方向，因为有机会将ivosidenib 与其他协同药物联合使用，包括标准化疗 (CT)、免疫检查点抑制剂 (ICI) 和 IDH2 抑制剂。
