Zanidatamab in HER2-Positive Advanced Biliary Tract Cancer
In this article
Advances in technology and medical knowledge have increased the importance of targeted approaches in cancer treatment. By targeting specific biological features of disease, these treatments can improve quality of life and survival. This article discusses a study investigating the effectiveness and safety of zanidatamab, a new option for patients with HER2-positive advanced bile duct cancer. Bile duct/biliary tract cancer is difficult to treat, particularly at advanced stages, creating a need for new, more effective treatments.
HER2 (Human Epidermal Growth Factor Receptor 2) is a receptor that can stimulate cell growth and division in many cancers. HER2 overexpression or gene amplification (an increased number of gene copies in DNA) occurs in various cancers, particularly breast and stomach cancers.
HER2 positivity is less common in bile duct cancers, but it occurs in a specific patient subgroup. HER2 mutations or gene amplifications occur in 17.4% - 18.5% of extrahepatic biliary tract cancers, 19.1% - 31.3% of gallbladder cancers and 3.7% - 4.8% of intrahepatic biliary tract cancers.
These rates indicate the potential applicability of HER2-targeted treatments in bile duct cancers.
The Largest Phase 2 Study of a HER2-Targeted Agent in Bile Duct Cancer
Lancet Oncology published HERIZON-BTC-01, a phase IIb study and the largest phase 2 trial of a HER2-targeted agent in bile duct cancer. Dr. James J. Harding and colleagues found that zanidatamab was effective in previously treated patients with HER2-positive advanced bile duct cancer.
How Does Zanidatamab Work?
Zanidatamab is a bispecific antibody targeting human epidermal growth factor receptor 2 (HER2). Bispecific antibodies can recognize two different targets simultaneously. Zanidatamab binds to two antigen-binding sites on its chosen HER2 receptor: the HER2 dimerization domain and the extracellular juxtamembrane domain.
This structure helps zanidatamab cross-link HER2 molecules and cluster receptors on the cell surface, promoting receptor internalization and reducing HER2 signaling activity. This controls cancer cell growth and proliferation because HER2 stimulates growth and division in certain cancers.
Zanidatamab also activates immune mechanisms called Antibody Dependent Cellular Cytotoxicity (ADCC), Antibody Dependent Cellular Phagocytosis (ADCP) and Complement Dependent Cytotoxicity (CDC).
ADCC refers to the ability of antibodies to kill target cells through specialized cells, such as natural killer cells. Zanidatamab directs the immune system's natural killer cells to destroy target cells, in this case cancer cells overexpressing HER2. ADCP refers to antibodies' ability to engulf target cells, generally with cells such as macrophages and dendritic cells. CDC refers to antibodies' ability to kill target cells through specialized proteins that are part of the complement system.
In preclinical studies, zanidatamab showed greater antitumor activity than trastuzumab alone or combined with pertuzumab. It is therefore a potential candidate for treating HER2-positive cancers.
Clinical Trial Details
The study enrolled 87 patients with locally advanced or metastatic biliary tract cancer that had progressed on gemcitabine-based chemotherapy, from Canada, Chile, China, France, Italy, South Korea, Spain, the United Kingdom and the United States.
Patients were divided into two groups by HER2 immunohistochemistry (IHC) score:
- Cohort 1 (80 patients; IHC 2+ or 3+ = HER2-positive), and
- Cohort 2 (n = 7 patients; IHC 0 or 1+).
In Cohort 1, 65% were Asian and 89% had stage 4 cancer. Since fewer tumors with HER2 IHC 0 or 1+ were identified than expected, enrollment in Cohort 2 stopped once Cohort 1 was fully enrolled. Patients received zanidatamab 20 mg/kg every 2 weeks.
Of the patients in Cohort 1:
- 51% had gallbladder cancer,
- 29% had intrahepatic biliary tract cancer (intrahepatic cholangiocarcinoma), and
- 20% had extrahepatic biliary tract cancer (extrahepatic cholangiocarcinoma).
The primary endpoint, assessed by independent central review in Cohort 1, was the confirmed objective response rate.
Responses
- At the October 2022 data cutoff, median follow-up was 12.4 months (interquartile range = 9.4–17.2 months).
- In Cohort 1,
- an objective response occurred in 33 of 80 patients (41.3%, 95% confidence interval [CI] = 30.4%–52.8%), including 1 complete response (1.3%).
- Another 22 patients (27.5%) had stable disease,
- resulting in a disease control rate of 68.8% .
- Among responders, median response duration was 12.9 months (95% CI = 6.0 months to not estimable). At data cutoff, 16 responses (49%) were ongoing.
- Median progression-free survival was 5.5 months (95% CI = 3.7–7.2 months).
- Overall survival data were immature, but the 9-month overall survival rate was 69.9% (95% CI = 57.8%–79.1%).
No objective responses were observed in the seven patients in Cohort 2. Median progression-free survival was 1.9 months (95% CI = 1.2 months to not estimable), and median overall survival was 5.5 months (95% CI = 1.2–10.1 months).
Below, the study's subgroup analysis is shown:
Figure 1. Objective response rate (ORR) by independent central review across Cohort 1 (HER2-positive) subgroups. Reference lines indicate the overall cohort's 95% CI limits. ECOG PS=Eastern Cooperative Oncology Group performance status. IHC=immunohistochemistry. ORR=objective response rate.
Side Effects
Across all 87 patients, the most common treatment-related adverse events of any grade were diarrhea (37%), infusion-related reactions (33%), decreased ejection fraction (9%, reduced heart contraction strength) and nausea (9%). Grade 3 treatment-related events occurred in 16 patients (18%), with no grade 4 or 5 events observed; the most common were diarrhea (5%) and decreased ejection fraction (3%). Serious treatment-related events of any grade occurred in 8% of patients. Treatment-related events led to discontinuation in two patients, for decreased ejection fraction and pneumonitis.
Commentary
This phase 2 single-arm study evaluated zanidatamab's antitumor activity and safety in patients with HER2-positive bile duct cancer. Advanced bile duct cancer carries a poor prognosis. No HER2-targeted treatments are approved for this molecular subgroup, representing an important unmet need. The results showed that zanidatamab was well tolerated and had encouraging single-agent activity in response rate and response duration. This is the largest phase 2 trial of a HER2-targeted agent in bile duct cancer.
The findings support zanidatamab as a potential treatment for patients with advanced bile duct cancer with HER2 scores of 2+ or 3+. Based on these results, efforts continue to study zanidatamab in combination with first-line chemotherapy and as a monotherapy option for advanced bile duct cancer.
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