Podcast: The Deep Dive

Rivi and Todd provide their angle on this treatment option (11 mins)

When understanding comes early, options are preserved.

Most patients miss options not because they do not qualify, but because the biology was never fully identified in time.

FDA approval
On May 8, 2026, the U.S. Food and Drug Administration (FDA) approved BIZENGRI (zenocutuzumab-zbco) for adults with advanced unresectable or metastatic cholangiocarcinoma carrying an NRG1 fusion after prior systemic treatment.

This is the first FDA-approved targeted therapy specifically for NRG1 fusion-positive cholangiocarcinoma.

When you understand your biology early,
options are seen.

Biology

NRG1 fusion repeatedly reactivates the HER2/HER3 growth signalling pathway.

Physiology
The cell continuously receives instructions to grow, survive, and keep dividing.

Cognition (understanding)
BIZENGRI is designed to interrupt this abnormal signalling conduit.

This pathway only matters if the tumour carries an NRG1 fusion, and many standard genomic tests may miss it unless RNA fusion testing was included. This is why identifying the biology early matters.

NRG1 stands for Neuregulin 1.

It is a signalling gene involved in how cells communicate growth, repair, and survival instructions.

NRG1 is a gene that holds the instructions for making a signalling messenger protein.

Under normal conditions, this messenger acts like a key. It briefly binds to and activates HER3 growth receptors on the cell surface.

When HER3 partners with HER2, they form a signalling conduit that carries the growth instruction from outside the cell into the cell.

The instruction is delivered, the growth signal switches OFF, and the NRG1 messenger disengages.

This is normal controlled growth signalling.

In some cholangiocarcinomas, the NRG1 gene becomes damaged and abnormally fused with another gene.

This creates a new hybrid mRNA instruction that produces an abnormal NRG1 fusion protein.

Instead of switching OFF normally, the abnormal fusion protein repeatedly reactivates the HER3/HER2 signalling pathway.

The tumour cell is continuously told to:

• grow
• survive
• keep dividing

This repeated signalling contributes to uncontrolled tumour growth.

BIZENGRI is a laboratory-made bispecific antibody protein molecule given by infusion.

One side attaches to HER2 and the other attaches to HER3.

By preventing HER2 and HER3 from pairing together properly, the drug disrupts the signalling conduit needed to carry the repeated growth instruction into the tumour cells.

This pathway is only for patients whose tumour carries an NRG1 fusion.

Patients generally need:

• Confirmed NRG1 fusion-positive cholangiocarcinoma
• Advanced or metastatic disease
• Previous treatment already received
• Comprehensive genomic profiling confirming the fusion

Importantly, many standard genomic tests may miss NRG1 fusions unless RNA fusion testing is included.

If you are unsure:
Ask your oncologist or molecular testing provider directly whether RNA fusion analysis was performed.

BIZENGRI (zenocutuzumab) has now received FDA approval in the United States for advanced NRG1 fusion-positive cholangiocarcinoma after prior systemic treatment.

At present:

• FDA approved in the United States
• Not currently TGA approved in Australia
• Access outside the U.S. may depend on clinical trials, compassionate access, or special access pathways

Because NRG1 fusions are extremely rare, availability may continue expanding internationally over time.

If your tumour carries an NRG1 fusion:

• Ask your oncologist about current access pathways
• Ask whether overseas referral or compassionate access programs exist
• Confirm whether any active NRG1-related clinical trials are recruiting globally

The first step is still identifying the fusion correctly.

The FDA approval was based on the eNRGy clinical trial in patients whose tumours carried an NRG1 fusion.

About one-third of patients experienced meaningful tumour shrinkage after treatment.

That matters because these patients had already progressed after previous treatment and carried a rare signalling pathway continuously driving tumour growth.

Some patients also experienced periods where the cancer remained controlled for extended time before progressing again.

The median progression-free survival was approximately 9 months.

In simple terms:

The drug was able to slow or reduce tumour growth in a portion of patients by disrupting the abnormal HER2/HER3 growth signalling conduit being repeatedly reactivated by the NRG1 fusion.

This is important because targeted therapies like this are designed to interfere with the specific biological engine driving the cancer.

But it is equally important to remain grounded.

This is not currently being presented as curative.

Durable complete responses have not yet become the defining story here.

At present, this appears more like targeted tumour control by disrupting the abnormal growth signalling pathway driving the tumour.

Understanding NRG1 matters because the same signalling pathway driving tumour growth may also create a therapeutic vulnerability.

For the right patient, this opens another treatment pathway, but only if the biology is recognised in time.

NRG1 fusions are rare and can easily remain invisible unless comprehensive genomic profiling and RNA fusion testing were performed properly.

This is where many patients lose options, not because the pathway does not exist, but because the fusion was never identified early enough.

The risk is not that this pathway is rare.

The risk is missing it completely because the biology was never fully investigated.

Treatment involves receiving BIZENGRI (zenocutuzumab) as an intravenous infusion under specialist oncology supervision.

Patients typically require:

• Ongoing monitoring
• Regular imaging scans
• Blood testing
• Review of treatment response and side effects

This is now an FDA-approved targeted therapy for NRG1 fusion-positive cancers, including cholangiocarcinoma, after previous treatment.

It is important to remain grounded:

• This is not currently being presented as curative
• Durable complete responses have not yet become the defining story here
• This appears more like targeted tumour suppression rather than deep immune eradication

The risk is not the treatment.
The risk is missing the biology before the pathway can even be seen.

Confirm whether comprehensive genomic profiling has been performed
Ask specifically whether RNA fusion testing was included
Confirm your NRG1 fusion status
Obtain copies of all genomic reports
Review all findings carefully with your treating team
Important:

This is currently an FDA-approved treatment pathway in the United States.

It is not currently an approved treatment pathway in Australia, and there are no currently known Australian NRG1-specific cholangiocarcinoma trials recruiting at this time.

Access in Australia may depend on:

• future clinical trials
• compassionate access pathways
• special access programs
• overseas treatment pathways

The first step is still identifying the biology correctly before options can even be explored.

BIZENGRI (zenocutuzumab) received FDA approval in the United States in May 2026 for previously treated unresectable or metastatic NRG1 fusion-positive cholangiocarcinoma.

This approval was based on clinical trial data demonstrating activity in patients whose tumours carried an NRG1 fusion.

At this time:

• the treatment is FDA approved in the United States
• it is not currently TGA approved in Australia
• no current Australian NRG1-specific cholangiocarcinoma trial sites are publicly confirmed

Access pathways outside the United States may depend on:

• compassionate access programs
• special access schemes
• international referral pathways
• future regulatory approvals and trials

Because this is a rare molecular subgroup, international availability may continue evolving over time.

If NRG1 is not seen, it cannot become an option.

This is not a treatment pathway for all cholangiocarcinoma.

It is for a very small subgroup whose tumour carries an NRG1 fusion.

The challenge is that many patients may never know the fusion is there unless comprehensive genomic profiling and RNA fusion testing were performed properly.

For the right patient, identifying this biology may open a pathway that otherwise would never have become visible.

That is why understanding the biology early matters.

Written by Steve Holmes
Founder, Cholangiocarcinoma Foundation Australia

We are a patient-led community built around one reality: understanding early keeps options open.

Clinical trials, biomarkers, genomic profiling, and targeted therapies only matter if the biology is identified before time is lost.

What you do next matters.