A Precision Response to FGFR2 Fusion in Cholangiocarcinoma

Name: Pemigatinib

Brand Name: Pemazyre

Company: Incyte Corporation

Type: Targeted Therapy (FGFR Inhibitor)

Form: Oral tablet

Cycle: 14 days on, 7 days off — repeat every 21 days

Role: The Circuit Breaker

The Circuit Breaker – a small-molecule drug taken as a tablet that blocks the FGFR2 receptor, which acts like a satellite dish mounted on the outside of your cells. Pemazyre acts like a blackout cover — sealing off these receptors and cutting the rogue signal chain that drives uncontrolled cell growth.

Now that we’ve seen how Pemazyre works, let’s take a closer look at the FGFR2 gene and the receptor it builds — the one Pemazyre is designed to block.

FGFR2 is like a blueprint stored in City Hall — your cell’s nucleus. It holds the DNA instructions for building FGFR2 receptors — the satellite dishes mounted on the cell’s surface that receive growth signals from the body.

When needed, City Hall activates the FGFR2 file, and sends its blueprint through mRNA — the city’s planners and couriers. These planners carry the instructions to ribosomes, the city’s protein factories, which build the FGFR2 satellite dishes.

In a healthy cell, this process only happens when the city needs to grow — like adding antennas when a suburb expands.

But when the FGFR2 gene in the nucleus fuses with another gene, due to damage and heat stress in the DNA, it loses control. Its message signalling can become stuck in the on position.

The mRNA planners start racing out nonstop, ordering more and more satellite dishes to be built — even when the city is overcrowded. The cell becomes overwhelmed by growth signals, and tumour growth begins.

Pemazyre doesn’t fix the blueprint or stop the mRNA messages — instead, it acts downstream: covering the satellite dishes on the cell surface, so they can’t receive or relay the “grow more” messages.

In many cases of intrahepatic cholangiocarcinoma, cancer begins not with a sudden crisis — but with silent, repeated damage to the epithelial cells that line your bile ducts.

This damage is often caused by changes in your bile — when it becomes thick, toxic, or acidic due to lifestyle, inflammation, or other chronic stressors. That toxic bile washes across the inner walls of your ducts, irritating and injuring the epithelial lining over and over again.

Each injury triggers a response from the cell’s internal repair crews — a sophisticated immune team that rushes in to patch up the damage. But when the attacks keep coming, day after day, those crews start to fall behind. Repairs become rushed. Mistakes start to creep in.

Each repair fuels inflammation. And inflammation generates heat — inside the very cells it was meant to protect.

That heat builds stress, and stress destabilises the DNA within the cell’s nucleus — the city’s central command. Eventually, under enough pressure and chaos, two genes that sit near each other can become fused together.

In this case, it’s often the FGFR2 gene that fuses with another gene nearby — creating a new, unregulated gene with faulty instructions.

This new fusion gene starts sending out endless orders to build more FGFR2 receptors — like installing far too many satellite dishes on the cell’s surface.

Even when no growth signals are being sent by the body, these dishes pick up background noise and convert it into action.

Growth becomes constant. Unchecked. And eventually, uncontrolled.

And when the immune system can no longer correct the error — when the cell’s repair tools finally fail — that damaged cell crosses a threshold.

It doesn’t return to normal.

It becomes mutated. It becomes cancer.

And when that mutated cell divides, it creates another faulty version of itself — and then another.

That’s how the tumour begins to build.

• FGFR2 Fusions are found in approximately 10–15% of patients with intrahepatic cholangiocarcinoma (iCCA)
• Used when an FGFR2 fusion is confirmed through genomic testing (such as NGS)
• Typically prescribed in advanced, unresectable, recurrent, or metastatic settings
• Other FGFR inhibitor drugs include:
  • Futibatinib (Lytgobi)
  • Infigratinib (Truseltiq)

How Long Do Patients Stay on Pemazyre?

Most patients remain on Pemazyre for several months, but the actual duration varies widely:

Some stop early, within 1–3 cycles — due to side effects or lack of benefit

Others continue for 6–12 months or longer if:

• The cancer remains stable or responds
• Side effects are manageable
• The patient maintains overall well-being

Treatment usually stops when:

• The cancer starts growing again (e.g., new mutations bypass the drug)
• Side effects become unmanageable
• Quality of life declines, or personal goals shift

Why Does Pemazyre Treatment End?

• Disease progression – the cancer adapts, and FGFR2 receptors change shape, making the drug less effective
• Toxicity accumulation – side effects build up, and recovery time between cycles becomes harder
• Patient-led decisions – the physical or emotional toll may outweigh the perceived benefit

Treatment decisions are continually re-evaluated based on benefit versus burden — and that balance evolves over time.

These side effects are documented in clinical trials and post-approval data.

Common Side Effects

• Dry mouth (xerostomia)
• Dry eyes or visual discomfort
• Fatigue
• Diarrhoea
• Changes in nails (brittleness, lifting)
• Loss of appetite
• Altered taste
• Hair thinning
• Skin or hand-foot irritation
• Elevated phosphate levels in the blood (hyperphosphataemia)

Less Common but Serious Side Effects

• Retinal changes (e.g., retinal pigment detachment)
• Elevated liver enzymes
• Kidney function decline
• Joint or muscle pain
• Mouth ulcers

What to Expect in Cycle One

In the first 21-day cycle (14 days on, 7 days off), many patients begin to experience side effects around Day 5 to Day 10, with symptoms intensifying as the drug accumulates in the system.

The most commonly reported early effects include:

• Fatigue – often described as a dragging tiredness, not relieved by rest
• Dry mouth – noticeable discomfort, especially at night
• Diarrhoea – mild to moderate, often managed with diet or anti-diarrhoeal medication
• Changes in taste – food may taste metallic or bland
• Loss of appetite – a general disinterest in eating, or nausea
• Mild eye discomfort – dryness, blurring, or light sensitivity (usually manageable but may need eye drops)
• Nail changes or skin dryness – not always immediate, but can emerge during or after the first cycle

Plan for Fatigue

• Lighten your commitments in the first two weeks
• Accept help with meals, errands, or daily tasks
• Build in regular rest periods, even if you don’t feel tired at first

Stay Ahead of Dry Mouth

• Keep water or sugar-free lozenges nearby
• Avoid spicy or salty foods early in the cycle
• Maintain regular dental hygiene and consider a dry mouth rinse

Support Your Gut

Ensure you include small amounts of fat in each meal — such as olive oil, avocado, egg yolk, full-fat dairy, fatty fish (like salmon or mackerel), or animal fats (butter, beef tallow, lamb fat). These trigger bile release and flow, allowing your body to form micelles — essential for absorbing fat-soluble vitamins (A, D, E, and K). Bile release also helps reduce ductal pressure and prevents sediment build-up (sludge).

Avoid ultra-low-fat diets unless medically directed, as they can impair nutrient absorption and bile clearance.

Eat smaller, more frequent meals (3–5 per day) to reduce digestive pressure and maintain steady nutrient delivery.

If diarrhoea begins, switch to bland, low-fibre foods and check with your clinician before using over-the-counter treatments like loperamide.

Fat’s Role in Bile, Nutrition, and the Vicious Cycle

Think of fat as the delivery vehicle that carries essential vitamins (A, D, E, and K) — the ones your pancreatic enzymes have unlocked from food.

But those vitamins can only be absorbed if bile is present and flowing.

No fat = no bile. No bile = no absorption.

The nutrients stay in your gut and pass straight through — unused — increasing the risk of malnutrition and anemia.

When those nutrients aren’t absorbed, your liver is deprived of the very building blocks it needs to produce healthy bile.

Without them, bile composition begins to suffer — and so does everything downstream.

Poor bile composition is the root failure point.

It leads to:

Sludge buildup
Rising toxicity
Increased pressure in the ducts
Ongoing damage and inflammation to the epithelial lining
Blocked nutrient absorption
These effects compound into a vicious cycle — where even a perfect diet can lead to cellular malnutrition.

And most patients are never told this — even though it could change everything.

Without those fat-soluble nutrients, your liver can’t produce healthy bile.

The system chokes on itself.

Disclaimer:
This information is intended for educational purposes only. Always consult your medical team or dietitian before making changes to your fat intake or nutrition strategy — especially during treatment, or if you have a liver, gallbladder, or pancreatic condition.

Monitor Vision Changes

– Book a baseline eye test before starting treatment
– Use preservative-free lubricating eye drops if dryness begins
– Report any blurring or visual changes immediately

Prioritise Blood Tests and Hydration

– Your team will monitor your **phosphate levels** and organ function
– Aim for consistent hydration (especially during warm weather or diarrhoea)

The best preparation is communication. Report side effects as soon as they appear — don’t wait. Many can be managed before they become disruptive.

Now apply what you’ve learned. Ask these questions to stay in control of your journey — and ensure you stay in the driver’s seat.

These help you personalise what you’ve just learned:

• Is Pemazyre being used on its own — or alongside other treatments?
• How will we track if it’s working in my case?
• If side effects arise, how quickly can we adjust the dose or manage symptoms?
• If Pemazyre stops working, what’s our plan — clinical trials or other FGFR inhibitors?
• Do I need to make any nutrition or lifestyle changes to support bile flow and recovery?

FGFR2 (Fibroblast Growth Factor Receptor 2)

A growth signal receptor on the outside of cells.

FGFR2 is like a satellite dish mounted on the surface of a cell. Its job is to receive specific growth instructions from messenger proteins called Fibroblast Growth Factors (FGFs). When activated, it tells the cell to grow or divide. In some cancers like intrahepatic cholangiocarcinoma, the FGFR2 gene fuses with another gene and gets stuck in overdrive — producing far too many receptors and sending constant grow-more messages.

Fibroblast

The body’s structural repair crew.

Fibroblasts are specialised cells that help build and repair connective tissue. Think of them as construction workers that maintain your body’s infrastructure — especially after injury or inflammation. They follow growth instructions from proteins called Fibroblast Growth Factors (FGFs).

Fibroblast Growth Factors (FGFs)

Messenger proteins that instruct cells to grow, heal, or repair.

These signals are normally well-controlled and help with healing and development. But when the FGFR2 system is hijacked (like in FGFR2 fusion cancers), these signals can fuel tumour growth.

FGFR2 Fusion

When the FGFR2 gene fuses with another gene — and won’t turn off.

This fusion causes the gene to send out nonstop build instructions to create FGFR2 receptors (the satellite dishes). The more dishes, the more signals are received — leading to uncontrolled tumour growth.

Pemazyre (Pemigatinib)

A targeted therapy that blocks rogue FGFR2 signals.

Pemazyre works like blackout covers placed over the satellite dishes (FGFR2 receptors), blocking them from receiving or passing on growth instructions. It’s used when FGFR2 fusion is confirmed by genomic testing.

Micelles

Tiny transport bubbles that carry fat-soluble nutrients.

Formed when bile and fat mix in your gut. These allow your body to absorb vital nutrients like vitamins A, D, E, and K. Without fat, micelles can’t form, and those nutrients pass through unused.

Bile

A digestive fluid made by your liver.

Bile helps break down fats and is essential for forming micelles. It also carries waste products out of the body. Good bile flow and composition are vital for digestion and liver health.

Sludge

Thickened bile that builds up when flow is poor.

Like sediment in a blocked pipe, sludge can lead to pressure, infection, and further damage in bile ducts — especially when bile is produced but not released (e.g., due to lack of fat in meals).

mRNA (Messenger RNA)

The delivery worker inside Cell City.

mRNA carries instructions from DNA (in the cell’s nucleus) to the ribosome (the factory), where proteins like FGFR2 receptors are built.

Ribosome

The protein factory inside the cell.

Receives blueprints from mRNA and builds what’s needed — like FGFR2 receptors in this case.

Epithelial Cells

The protective lining inside your bile ducts.

These are the first cells hit by toxic bile or inflammation. Repeated damage here leads to mutations and can trigger cancer.

Mutation

A permanent change to the DNA.

Mutations can be caused by chronic inflammation, toxins, or other damage. Some mutations give cells new — and dangerous — abilities, like uncontrolled growth.

Tyrosinase – an enzyme involved in melanin production (skin pigmentation), not related to FGFR2, bile, or cancer growth signalling.

Tyrosine kinase – very relevant here. FGFR2 is a receptor tyrosine kinase, meaning:

• It’s a type of receptor on the cell surface.
• When activated (by binding a growth factor like FGF), it adds a phosphate group to tyrosine residues on proteins inside the cell.
• This phosphorylation sends a cascade of growth signals into the cell.

Disclaimer
This information is shared patient to patient. It reflects my personal experience and deep engagement with the bile duct cancer journey. While I’ve worked to ensure accuracy and clarity, this content is not medical advice. Always consult your healthcare team for guidance specific to your situation.