Introduction
Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary malignant tumor of the liver, with approximately 8,000 cases diagnosed annually in the United States, accounting for only 3% of gastrointestinal malignancies diagnosed worldwide each year. The incidence of ICC has increased over the past few decades, with some studies indicating a 14% annual increase since the early 1990s.
The rising incidence of ICC may be attributed to the increasing global prevalence of hepatitis C virus infection, as well as obesity-related non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which are known risk factors for ICC. There are also regional differences in the risk factors associated with ICC; for example, patients with ICC in Eastern countries have a significantly higher relative incidence of liver stones, liver fluke infection, and viral hepatitis. In contrast, in Western countries, ICC is more commonly associated with primary sclerosing cholangitis and other chronic liver diseases (non-alcoholic fatty liver, non-alcoholic steatohepatitis, and cirrhosis).
Currently, treatment for ICC remains challenging as most patients with advanced disease are not candidates for therapeutic surgical resection. Even among operable patients, complete surgical clearance is difficult to achieve, and the recurrence rate remains high. Therefore, systemic chemotherapy and targeted therapy for ICC have garnered significant attention. Over the past decade, understanding the molecular and genetic basis of ICC has changed treatment approaches and strategies, with next-generation sequencing showing that most ICC tumors harbor at least one targetable mutation. These advances have facilitated numerous clinical trials to examine the safety and efficacy of novel therapies targeting tumor-specific molecules and genetic alterations. Although some clinical trials have shown promising results, large-scale randomized studies are still needed to further determine the potential clinical value of such treatments.
Mechanism of ICC
ICC is most commonly associated with chronic biliary inflammation and stasis. Therefore, patients with diseases that promote chronic bile stasis and inflammation (primary sclerosing cholangitis, liver stones, liver fluke infection, chronic hepatitis, and cirrhosis) are at risk for developing ICC.
Common genetic mutations associated with ICC include KRAS, BRAF, TP53, and epidermal growth factor receptor. KRAS mutations are the most common mutations associated with ICC; however, their incidence varies from 8% to 53%. BRAF mutations are also common, with an incidence reported in ICC tumors ranging from 0-22%. Patients with tumors harboring KRAS or BRAF mutations have poorer median survival than those with wild-type tumors (23 months and 34 months, respectively, p=0.05). Compared to patients with BRAF-mutated ICC tumors, those with KRAS mutations also have a worse five-year overall survival rate (13.5 months vs. 23.2 months, p=0.05).
Recently, two major biological types of ICC have been identified: inflammatory and proliferative. Inflammatory ICC accounts for 38% of ICC cases, characterized by the activation of pro-inflammatory signaling pathways through various cytokines such as IL-10, IL-4, and IL-6, and STAT3. Proliferative ICC accounts for 62% of ICC cases, characterized by the activation of oncogenic signaling pathways, particularly through receptor tyrosine kinases (RTK). The primary types of mutations driving RTK dysfunction are gain-of-function mutations (EGFR), overexpression of RTKs, and genomic amplifications (EGFR, MET), chromosomal rearrangements, and constitutive activation of kinase domains.
There are several important differences in the clinical phenotypes of inflammatory and proliferative ICC. For example, proliferative ICC tumors are more likely to be moderately to poorly differentiated, while inflammatory tumors are more likely to be well-differentiated. Survival analysis of proliferative and inflammatory ICC indicates that patients with proliferative ICC have shorter recurrence times (15 months vs. 37 months, p=0.03) and lower median survival (24.3 vs. 47.2, p=0.048). Additionally, the incidence of KRAS mutations in proliferative ICC tumors is 8%, while in inflammatory ICC tumors, it is 7%; the incidence of BRAF mutations in proliferative ICC tumors is 5%, and in inflammatory ICC tumors, it is 2%.
Biomarkers of ICC
The advancement of next-generation DNA sequencing technology has changed the treatment landscape for many different types of cancers, including ICC. In fact, up to 70% of ICC tumors may have at least one targetable genetic mutation, with an average of 1 to 2 targetable mutations per examined tumor.
Several early small studies have found that the most common mutations in ICC include ARID1A (36%), IDH1/2 (36%), TP53 (36%), and MCL1 (21%). Common actionable mutations (with FDA-approved drugs available for treatment) include FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2B (7%), ERBB3 (7%), MET (7%), NRAS (7%), CDK6 (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%) genes.
The expression of programmed death ligand 1 (PD-L1) has also been reported in 10–70% of ICC tumor specimens, with PD-L1 positivity associated with more aggressive ICC features and poorer survival rates. Although rare, microsatellite instability (MSI) has been explored as a biomarker and target for personalized ICC treatment. Due to the rarity of MSI in ICC, definitive conclusions about its incidence and prognostic impact have been difficult to interpret. Existing data suggest that microsatellite unstable tumors (defined as the loss of DNA mismatch repair proteins MLH1, PMS2, MSH2, MSH6) are uncommon, occurring in only a small number of ICC patients (1-10%).
Targeted Therapy for ICC
Despite the discovery of various genetic mutations in ICC, the low incidence of many mutations poses challenges for the use of targeted therapies. However, early clinical trials have begun for some more common genetic mutations, including those involving IDH1/2, FGFR, EGFR, and VEGF.
Isocitrate Dehydrogenase
Due to the presence of IDH1/2 mutations in approximately 10–20% of ICC lesions, this genetic mutation has been a target for therapeutic intervention. In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, the safety and efficacy of the mutant IDH1 inhibitor Ivosidenib were studied in patients with advanced cholangiocarcinoma progressing on fluorouracil or gemcitabine-based chemotherapy. The trial included patients with all types of cholangiocarcinoma (i.e., intrahepatic, hilar, distal); however, most patients had ICC (89% in the treatment group, 77% in the placebo group). Among 185 patients (124 in the treatment group, 61 in the placebo group), Ivosidenib was associated with improved progression-free survival (median 2.7 months vs. 1.4 months, p<0.0001) and comparable safety (30% of patients in the treatment group experienced serious adverse events vs. 22% in the control group).
Fibroblast Growth Factor Receptor
FGFR abnormalities have been found in 10-15% of ICC tumors, with FGFR expressed on various cell types, consisting of four transmembrane receptors (FGFR1-4) with intracellular tyrosine kinase domains. Binding of these FGFR receptors leads to uncontrolled activation of various cell proliferation pathways, including RAS-Raf MAPK, JAK-STAT, and PI3-AKT mTOR, resulting in angiogenesis and uncontrolled cell proliferation.
Pemigatinib is an oral kinase inhibitor that inhibits FGFR 1, FGFR2, and FGFR3. Several phase 2 clinical trials have assessed the safety and anti-tumor activity of Pemigatinib in patients with advanced cholangiocarcinoma with FGFR rearrangements. In one trial, among 146 registered patients, 35% had objective treatment responses, 42% of patients died due to disease progression, and 45% experienced serious adverse events. Pemigatinib is currently undergoing a phase 3, open-label, randomized, active-controlled multicenter trial comparing the efficacy and safety of Pemigatinib with standard treatment (gemcitabine-cisplatin) in patients with advanced or metastatic cholangiocarcinoma with FGFR2 alterations (NCT03656536).
Futibatinib is a different highly selective irreversible oral FGFR 1-4 inhibitor. Its efficacy and safety have been studied in a multicenter phase 2 clinical trial, where 34% of the 103 registered patients had objective responses, and the disease control rate to date is 76%, with 73% of patients experiencing serious adverse events (>=3 grade). In another multicenter phase 3 study (NCT04093362), Futibatinib is currently being compared with standard treatment (gemcitabine-cisplatin).
Additionally, many other early studies are testing the safety and efficacy of FGFR inhibitors targeting mutations.
Epidermal Growth Factor Receptor
The HER tyrosine kinase family includes EGFR and HER1-4, with EGFR mutations found in 25% of ICC tumors. EGFR is a subclass of transmembrane receptors with tyrosine kinase activity, binding to epidermal growth factor and activating signaling pathways involved in cell motility, cell adhesion, angiogenesis, and invasion.
Several early trials are underway to study the safety and efficacy of EGFR and HER inhibitors (lapatinib, erlotinib, pertuzumab, trastuzumab) in cholangiocarcinoma and other solid tumor patients, but significant objective treatment responses have not yet been demonstrated.
Immune Checkpoint Inhibitors
PD-L1 has been found in 10–70% of ICC tumor specimens, with its expression associated with tumor aggressiveness and reduced survival rates. The safety and efficacy of many PD-L1 inhibitors have been tested in advanced or metastatic PD-L1 positive cholangiocarcinoma. These early trials have not confirmed specific drug-related benefits, but preliminary results do suggest potential for treatment efficacy and safety.
Currently, many ongoing early trials are testing the efficacy and safety of immune checkpoint inhibitors in the treatment of advanced MSI-ICC patients.
BRAF Mutations
BRAF mutations occur in 5-7% of ICC cases. BRAF is a member of the RAS-RAF-MEK-ERK pathway (MAPK), and BRAF mutations are associated with higher TNM staging, resistance to systemic chemotherapy, and poorer survival rates. Many studies on targeted therapies related to BRAF-positive ICC are “bucket” studies, including many different types of solid tumors with BRAF mutations. Therefore, interpreting these data and identifying disease-specific efficacy has remained a challenge. Currently, some ongoing trials are being conducted on patients with metastatic cholangiocarcinoma, with results still pending.
Conclusion
In recent decades, significant progress has been made in understanding the molecular and genetic mechanisms of ICC. This evolving knowledge has facilitated the development and research of novel targeted therapies for patients with advanced ICC, some of which show enormous potential related to disease progression and even survival rates.
These results still need to be validated in larger clinical trials, and genetic analysis should be performed on these ICC patients to identify potential targeted therapies. Furthermore, as with many rare diseases, more appropriate patient participation in clinical trials is needed to help better define the role, efficacy, and safety of targeted therapies for ICC.
References:
1. Intrahepatic Cholangiocarcinoma: A Summative Review of Biomarkers and Targeted Therapies. Cancers (Basel). 2021 Oct; 13(20): 5169.
Source: Xiaoyao Talks Medicine