Newest Therapies for Cholangiocarcinoma: An Updated Overview of Approved Treatments with Transplant Oncology Vision

Abstract

A minority of cholangiocarcinoma (CCA) can be cured by surgical intervention (i.e., liver resection (LR) and liver transplantation (LT)). When modern criteria for LT are met, this intervention along with neoadjuvant treatments may achieve unprecedented survival in selected patients. Liver resection is associated with a median overall survival (OS) of 40 months, this number drastically decreases for unresectable advanced cholangiocarcinoma (CCA), which is treated with systemic therapy. The first-line chemotherapy regimen of gemcitabine and cisplatin is associated with a median overall survival of only 11.7 months. Since the Food and Drug Administration (FDA)'s approval of the isocitrate dehydrogenase (IDH) 1 inhibitor ivosidenib in August 2021, there has been increasing interest in targeted therapy for CCA patients harboring mutations in fibroblast growth factor receptor (FGFR) 2, neurotrophic receptor tyrosine kinase (NTRK), B-raf kinase (BRAF), and HER2. At the same time, immunotherapy with immune checkpoint inhibitors isalso being used in relapsed CCA. This review looks into the most recently completed and ongoing studies of targeted therapy as monotherapy or in combination with chemo- and/or immunotherapy. Whether it is resection, liver transplant, radiotherapy, chemotherapy, immunotherapy, targeted therapy, or any combination of these treatment modalities, great strides are being made to improve outcomes for this challenging disease.

Keywords: cholangiocarcinoma; immunotherapy; targeted therapy; transplant oncology.

Figure 1

Mutation frequencies in iCCA. From the most common to the least common, ranges of frequencies of targetable mutations in Isocitrate dehydrogenase (IDH) 1/2, fibroblast growth factor receptor (FGFR)2, HER2/ERBB2, B-raf kinase (BRAF), and neurotrophic receptor tyrosine kinase (NRTK) 1-3 are provided.

Figure 2

Targeting mutated (mut) isocitrate dehydrogenase (IDH) 1 and 2 in iCCA. α-KG: alpha-ketoglutarate; 2HG: 2-hydroxyglutarate.

Figure 3

Molecular pathways in iCCA. Inhibitors have been developed for well-known signaling pathways including the Raf/MEK/ERK, PI3K-AKT, and JAK/STAT pathway. AKT: protein kinase B; FGFR: fibroblast growth factor; HER2: epidermal growth factor receptor 2; JAK: janus kinase; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase. NTRK: neurotrophic receptor tyrosine kinase.