What is Cholangiocarcinoma?

Cholangiocarcinoma, otherwise known as bile duct cancer, is a rare condition where malignant cells, i.e. cancer cells, form in the bile ducts, leading to a tumour. The bile duct is a network of small tubes, called ducts, that connect the gallbladder, liver, and small intestine, which are all parts of the digestive system.¹ 

How does the digestive system work?

This network begins in the liver, where numerous tiny ducts collect bile—a fluid produced by the liver to help digest fats. These small ducts merge into the right and left hepatic ducts, which exit the liver and join to form the common hepatic duct. The common hepatic duct connects to the gallbladder via the cystic duct, allowing bile from the liver to flow into the gallbladder for storage. During digestion, the gallbladder releases the bile it has stored. It travels through the cystic duct into the common bile duct and then empties into the small intestine to aid in breaking down fats.

What are the types of Cholangiocarcinoma (Bile Duct Cancer)?

Intrahepatic cholangiocarcinoma

A type of cancer that forms in the bile ducts inside the liver.²

Extrahepatic cholangiocarcinoma

A type of cancer that forms in the bile duct outside the liver. There are 2 main types of extrahepatic cholangiocarcinoma: perihilar cholangiocarcinoma and distal bile cholangiocarcinoma.^1,2 

Perihilar cholangiocarcinoma

This cancer is found in the area where the left and right bile ducts exit the liver to form the common hepatic duct.^1,2 

Distal cholangiocarcinoma

It is found in the area where the bile ducts from the liver and the gallbladder join to form the common bile duct, which then passes through the pancreas and ends in the small intestine.^1,2 

What are the signs and symptoms of cholangiocarcinoma?

There are a few main symptoms of bile duct cholangiocarcinoma to look out for:^1,2 

• Jaundice (skin or whites of eyes turning yellow)
• Pain in the abdomen
• Dark urine
• Clay coloured stool
• Fever
• Itchy skin
• Nausea and vomiting
• Weight loss for an unknown reason

What are the causes of Cholangiocarcinoma?

Cholangiocarcinoma occurs when cells in the bile ducts undergo changes in their DNA due to a genetic mutation. These genetic mutations are not the same in every individual.³

Intrahepatic cholangiocarcinoma 

Two of the most common changes (mutations) in this type of cancer are in the FGFR2 and IDH1 genes.

FGFR2 mutations 

These mutations are found in about 1 out of 10 individuals. When this happens, the cancer grows because the FGFR2 gene sends abnormal growth signals to the cells, leading to tumour growth. Medicines, such as Pemigatinib and Futibatinib, can block this pathway and help control the cancer.³

IDH1 mutations 

These mutations are observed in approximately 1 in 5 patients. This change causes cells to make a harmful substance, 2-hydroxyglutarate (2-HG), that pushes normal cells toward becoming cancerous, leading to tumour formation and cancer. Drugs such as Ivosidenib are designed to target this mutation and can be an effective treatment option.³

Extrahepatic cholangiocarcinoma 

In this cancer, other mutations are more common, such as changes in the KRAS and TP53 genes. As of right now, these mutations are difficult to treat with targeted therapies, but researchers are studying them to find better options.³

What are the treatments for Cholangiocarcinoma?

There are several different ways to treat cholangiocarcinoma; the treatment used is dependent on the individual. These treatments can range from surgery, chemotherapy, transplant and finally targeted drug therapies, which we will be focusing on today.^1,2

What are targeted therapies?

Targeted therapies are a type of treatment where drugs are used to identify and attack a specific cancer cell. Next, we will analyse the main targeted therapies used in cholangiocarcinoma.⁴

FGFR inhibitors

The Fibroblast Growth Factor Receptor (FGFR2) signalling pathway plays a vital role in normal cell growth, survival and tissue repair. When FGFR2 undergoes genetic mutations, called an FGFR2 fusion, which becomes persistently active without needing its usual growth signals, leading to uncontrollable cancer cell growth, and therefore tumour formation, particularly in intrahepatic cholangiocarcinoma.⁴

FGFR2 mutations are seen mostly in intrahepatic cholangiocarcinoma cases and are rarely found in other bile duct cancer types. These features make FGFR2-altered tumours especially susceptible to FGFR-targeted drugs.⁴

Over the last few years, several medicines have been developed to block the FGFR pathway:⁴

• Pemigatinib – the first drug approved (2020) for patients whose cancer has FGFR2 fusions. In a second-stage clinical trial, pemigatinib was granted FDA approval for the treatment of cholangiocarcinoma with FGR2 fusion⁴
• Futibatinib – a newer type of FGFR inhibitor, approved in 2022, that may help even when the cancer becomes resistant to earlier drugs. It is used for individuals with more advanced cholangiocarcinoma⁵
• Infigratinib – approved in 2021 by the FDA, though it is no longer widely available^4,5

How well do they work?

Many patients see their tumours shrink or stop growing. Pemigatinib, for example, has helped about 4 out of 10 patients respond to treatment, with cancer control lasting around 6–9 months on average. Futibatinib has shown similar or even slightly better results in some studies.^4,5,6

Side effects of these medicines can cause problems like hyperphosphatemia (high phosphate levels in the blood), eye irritation, nail or skin changes, diarrhoea, or fatigue. Most side effects can be managed with regular check-ups and supportive care.⁶

IDH inhibitors

Mutations in the IDH1 or IDH2 genes disrupt normal cell function, leading to the accumulation of a cancer-promoting substance 2-HG. This substance interferes with the DNA and cellular processes that normally control growth, which in turn helps cancer to develop and progress more. By targeting the mutated IDH enzyme, it’s possible to reduce 2-HG levels and restore healthier cell behaviour, decreasing cancer activity.^4,5,6

Ivosidenib

Ivosidenib is a drug that targets the IDH1 gene mutation, which is found in some cholangiocarcinomas. In a large clinical trial, 185 patients whose cancer had already been treated but had come back or spread, were randomly given Ivosidenib. The trial found that Ivosidenib worked on bile duct cancer patients, even in later-stage cancer patients, by slowing down/stopping cancer cell growth. In terms of side effects, most people tolerate Ivosidenib well, with the common side effects such as nausea, fatigue, and abdominal pain.⁶

Summary

Cholangiocarcinoma, or bile duct cancer, is a rare disease that can develop inside or outside the liver, with symptoms like jaundice, abdominal pain, and unexplained weight loss. Genetic changes in cancer cells, particularly FGFR2 and IDH1 mutations, play a key role in tumour growth and offer opportunities for targeted treatment. 

FGFR inhibitors, such as Pemigatinib, Futibatinib, and Infigratinib, work by blocking abnormal FGFR2 signals, helping to slow tumour growth in individuals with intrahepatic cholangiocarcinoma. IDH inhibitors, like Ivosidenib, target IDH1 mutations to reduce cancer-promoting substances and also slow disease progression. These targeted therapies can improve disease control and quality of life, often with manageable side effects. As research continues, new therapies and combination strategies are being explored to provide even more effective options for patients with cholangiocarcinoma.