Bispecific Ab for biliary tract cancer wins nod in KOR

HER2 targeting 'Ziihera' has emerged…expected to resolve the treatment gap for second-line treatments

Research on targeted therapies, such as FGFR·IDH1, is active…transition to precision medicine strategies accelerate

A targeted therapy with a new mechanism of action has emerged in the treatment landscape for biliary tract cancer. There is a strong trend moving away from the existing chemotherapy-centered approach toward biomarker-based precision medicine strategies.

Biliary tract cancer treatment 'Ziihera'

On the 19th, the Ministry of Food and Drug Safety (MFDS) approved BeOne Medicines' 'Ziihera (zanidatamab),' a treatment for human epidermal growth factor receptor 2 (HER2)-positive biliary tract cancer.

Ziihera was approved as a monotherapy for adult patients with unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer who have previously received at least one systemic therapy.

It is expected to become a new treatment option for a patient group that has had limited choices following previous therapies.

Ziihera is a bispecific antibody that simultaneously binds to two distinct sites (ECD2, ECD4) of the HER2 receptor.

The mechanistic characteristic of Ziihera is inducing tumor cell death by more potently inhibiting HER2 signaling while simultaneously activating various immune mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).

Ziihera is a new drug developed by the Canadian biopharmaceutical company Zymeworks. Subsequently, the U.S. company Jazz Pharmaceuticals licensed the development and commercialization rights for the substance from Zymeworks, and, under the contract, BeOne Medicines holds the commercialization rights in Asian regions, including Korea and China, excluding Japan.

This approval is highly significant, as it is the first bispecific antibody approved for biliary tract cancer. Analysis suggests that the treatment strategy targeting HER2 has become an option in clinical settings.

The approval was based on the results of the global Phase 2b 'HERIZON-BTC-01' study. According to the clinical results, the confirmed objective response rate (cORR) based on independent central review (BICR) in the HER2-positive IHC 3+ patient group (62 patients) was 52%.

The complete response (CR) was 3%, and the partial response (PR) was 48%.

The median duration of response (DOR) was 14.9 months, and among responding patients, 59% maintained the response for 6 months or longer, while 44% maintained it for 12 months or longer. In the overall HER2-positive patient group, the ORR was 41%, and the median overall survival (OS) was 15.5 months.

Regarding safety, the most commonly reported adverse events were diarrhea, infusion-related reactions, and anemia. Serious adverse events occurred in 47.7% of the subjects.

Biliary tract cancer, low survival rates·treatment gaps... will the shift to targeted therapy accelerate?

Biliary tract cancer occurs in the bile ducts through which bile is produced in the liver, and since early symptoms are not clear, a significant number of patients are diagnosed at an advanced stage. Because of this, it is considered a primary intractable cancer with a poor prognosis.

According to the South Korea Central Cancer Registry, the number of patients with biliary tract cancer in Korea increased by approximately 40%, from 5,444 in 2011 to 7,617 in 2021. Although the patient population is relatively small, treatment outcomes remain limited due to the difficulty of early diagnosis, rapid metastasis to surrounding organs, and high recurrence rates characteristic of the disease.

Targeted therapy for biliary tract cancer 'Tibsovo '

In fact, the 5-year relative survival rate (2017–2021) is only 28.9%, with more than 7 out of 10 patients reported to die.

Particularly in patients with unresectable locally advanced or metastatic biliary tract cancer, the limited treatment options available after the failure of first-line therapy have been pointed out as the largest unmet medical need in clinical settings.

Amid these treatment gaps, targeted therapy-based strategies have been rapidly expanding. Representative examples include Handok’s targeted therapies 'Pemazyre (pemigatinib)' for patients with FGFR2 fusion or rearrangement, and 'Tibsovo (ivosidenib)' for patients with IDH1 mutations.

FGFR genetic abnormalities are known to be involved in tumor cell proliferation, survival, angiogenesis, and drug resistance, while IDH1 mutations are reported with relatively high frequency in intrahepatic cholangiocarcinoma.

In fact, Tibsovo, which targets IDH1, improved progression-free survival (PFS) in the global Phase 3 ClarIDHy study, establishing itself as the first targeted therapy to succeed in a Phase 3 clinical trial in the biliary tract cancer field. However, unlike Pemazyre, there has been no news regarding reimbursement for Tibsovo since its domestic authorization in 2024.

As treatments targeting specific genetic mutations are introduced one after another, the addition of a HER2-targeted treatment strategy is shifting biliary tract cancer treatment toward a biomarker-based, multi-layered approach.

Furthermore, additional bispecific antibodies are awaiting commercialization. The bispecific antibody candidate 'tovesimig (HDB001A)', being developed by Compass Therapeutics in the U.S., recently achieved efficacy in the topline results of its global Phase 2/3 study.

Tovesimig is a new biliary tract cancer drug candidate developed by the Korean company ABL Bio. Handok holds the domestic rights, and Compass holds the global rights. This drug candidate is a bispecific antibody that simultaneously targets delta-like ligand 4 (DLL4) and vascular endothelial growth factor (VEGF), both of which promote the formation of new blood vessels in the tumor microenvironment.

According to the topline results, the ORR set as the primary endpoint was 17.1% for the tovesimig + Paclitaxel group, which was higher than the 5.3% of the Paclitaxel group. Additionally, progressive disease (PD) was 16.2% in patients co-administered tovesimig + Paclitaxel, whereas it was 42.1% in patients administered Paclitaxel alone.