"New targeted therapies for bile duct cancer are in need"

Do-Youn Oh, Professor of Department of Hematology-Oncology at Seoul National University Hospital

Treatment options have been limited for cholangiocarcinoma…new targeted therapies show effects in clinical trials

Tibsovo has been approved in South Korea…improved survival for patients who failed prior therapies

Do-Youn Oh, Professor of Department of Hematology-Oncology at Seoul National University Hospital

"Recently, as many companies have conducted various studies in the field of cholangiocarcinoma, effective drugs like Tibsovo have become available in the market.

 

Although the development of targeted therapy for cholangiocarcinoma was highly possible, like lung cancer, studies and investments have been insufficient until now.

 

We are seeing positive clinical outcomes recently." During a recent meeting with Daily Pharm, Do-Youn Oh, Professor of Department of Hematology-Oncology at Seoul National University Hospital, raised hope that effective targeted therapies are emerging for cholangiocarcinoma, a field with limiting treatment options until now.

 

Cholangiocarcinoma occurs when a cancerous tumor grows in the biliary duct that transports bile from the liver to the small intestine.

 

In South Korea, the number of patients with cholangiocarcinoma increased from 5444 patients in 2011 to 7617 in 2021, up 40% over ten years, based on the Korean Central Cancer Registry source last year.

 

Although the number of patients with cholangiocarcinoma is relatively small, the 5-year relative survival rate (2017-2021) is only 28.9% due to difficulties in early diagnosis, fast metastasis to nearby organs, and relapses.

 

Seven out of ten patients die from cholangiocarcinoma.

 

Another reason for the low survival rate for cholangiocarcinoma patients is a limited treatment option.

 

Until recently, there hasn't been a targeted drug that received domestic approval as a second-line treatment for patients with unresectable and locally advanced or metastatic cholangiocarcinoma who have failed first-line treatments.

 

Fortunately, Servier's Tibsovo (Ingredient: ivosidenib), a new targeted therapy, has been approved in South Korea in May.

 

Tibsovo can be used to treat adult patients with locally advanced or metastatic cholangiocarcinoma who test positive for isocitrate dehydrogenase-1 (IDH1) mutation.

 

Oh emphasized that new drugs can provide opportunities for patients.

 

Therefore, patient accessibility to targeted therapy must be higher.

 

The targeted therapy Tibsovo emerges…the only targeted therapy approved for treating cholangiocarcinoma with IDH1 mutation Tibsovo is the first-in-class targeted therapy to succeed in the global Phase 3 study for cholangiocarcinoma.

 

Of all solid cancers, IDH1 gene mutations mainly occur in glioma and cholangiocarcinoma.

 

In cholangiocarcinoma, IDH1 mutations are reported to mainly occur in the liver.

 

Oh said, "Without general characteristics, the second-line treatment options for cholangiocarcinoma are limited to either chemotherapy or FOLFOX (fluorouracil·leucovorin·oxaliplatin).

 

There are no standard medications for third-line treatments." Oh added, "However, patients with IDH1 mutations can be treated with targeted therapies.

 

If a patient maintains good condition, one can try various treatment options for cholangiocarcinoma." "IDH1 mutations are not frequently observed in next-generation sequencing (NGS) results when analyzing all biliary tract cancers, including intrahepatic cholangiocarcinoma and gallbladder cancer.

 

However, in the case of intrahepatic cholangiocarcinoma alone, the frequency of IDH1 mutations is approximately 10%," Oh explained.

 

The efficacy of Tibsovo was demonstrated in the Phase 3 ClarIDHy study, a randomized controlled trial involving cholangiocarcinoma patients with IDH1 mutations who had been treated previously.

 

Treating with Tibsovo resulted in a statistically significant improvement in the primary endpoint progression-free survival (PFS), based on the independent review committee.

 

Oh said, "Currently, standard medications are still unavailable for second-line treatments.

 

When the study for Tibsovo was in progress, even FOLFOX outcomes were not out yet.

 

Consequently, the placebo group was set as the control group." "We also proceeded the study by setting the primary endpoint as the progression-free survival (PFS).

 

It is because we designed the study so that the patients in the placebo group whose disease advanced could switch to Tibsovo.

 

If overall survival (OS) had been set as the primary endpoint, switching between treatments could dilute study outcomes due to the combined OS data," Oh added.

 

The study showed that the Tibsovo group had a median PFS of 2.7 months, whereas those in the placebo group had 1.4 months.

 

The percentages of patients whose disease did not process or result in death at 6 months or 12 months were found to be 32% and 22%, respectively, in the Tibsovo group.

 

No patients in the placebo group met these criteria.

 

Tibsovo showed positive results for the secondary endpoint, OS.

 

The Tibsovo group had a median OS of 10.3 months, while the place groups had 7.5 months.

 

Oh said, "Although the placebo group had 7.5 months OS, it was increased because the patient switched treatment to Tibsovo.

 

To account for this change, we used a rank-preserving structural failure time (RPFST), and an adjusted OD for the place group was 5.1 months.

 

The hazard ratio was significant (HR 0.49) when differences in OS of 10.3 months and 5.1 months were compared." Oh said, "Reviewing prescription outcomes, we have not observed any significant toxicity-related adverse reactions when patients were treated with Tibsovo.

 

For example, side effects of treatment with FGFR2 inhibitors include fissures found on fingers, bleeding, skin reaction, and nail loss.

 

In contrast, treatment with Tibsovo had no cautious side effects.

 

Consequently, patients can use the drug without worrying." More studies on effective targeted therapies are underway…"Need to improve patient accessibility" As many companies have recently increased their investments and conducted research into cholangiocarcinoma, effective drugs are gradually being released.

 

Recently, immune checkpoint inhibitors such as AstraZeneca's Imfinzi and MSD's Keytruda have been added as first-line treatments.

 

At the same time, Tibsovo has been introduced as a second-line treatment, extending survival times.

 

Oh said, "People often compare cholangiocarcinoma to non-small cell lung cancer (NSCLC).

 

Both cancers share the characteristic of having many genetic subtypes, which makes them similar in that regard.

 

Like lung cancer, cholangiocarcinoma is a type of cancer where various targeted therapies could be developed.

 

However, due to the relatively low number of patients, research and investment have been limited until recently.

 

With growing interest from the pharmaceutical industry, more promising research results are now emerging." However, even if the effects of medications were to be proven and approved, it takes a long time for patients to access those medications.

 

Professor Oh thinks patients need to understand the medication data and be provided with a clinical setting for ease of use.

 

Oh said, "In the case of cholangiocarcinoma, the meaning and value of differences in efficacy compared to existing drugs are much greater due to the lack of treatment options.

 

When interpreting data, it is crucial to consider each type of cancer's unique characteristics.

 

I hope the government will analyze and interpret the data with these specific characteristics in mind," adding, "In cancers with limited treatment options, the importance of a drug can differ significantly from cancers with many treatment options, and this should be understood when setting reimbursement criteria." "Over the last five years, the development of treatments for cholangiocarcinoma got fast.

 

Along with new drug development, many companies are focusing on developing drugs for cholangiocarcinoma.

 

Patients with cholangiocarcinoma need to follow physician's advice, receive treatments, and seize new opportunities such as participating in clinical trials."