Zanidatamab Demonstrates Durable Responses in HER2-Positive Biliary Tract Cancer, Earns FDA Accelerated Approval
核心洞察
Final results from the HERIZON-BTC-01 trial show zanidatamab achieved a 41.3% objective response rate with a median duration of response of 15.5 months in HER2 (搜索)-positive biliary tract cancer (搜索) patients.
Patients with the strongest HER2 (搜索) overexpression (IHC3+) experienced even greater benefit, with a 51.6% response rate and 18.1-month median duration of response.
The bispecific HER2 (搜索)-targeted antibody received FDA accelerated approval in November 2024 for treating previously treated, unresectable or metastatic HER2-positive biliary tract cancer (搜索).
Final results from the HERIZON-BTC-01 clinical trial demonstrate that zanidatamab, a bispecific HER2 (搜索)-targeted antibody, delivered clinically meaningful and durable responses for patients with HER2-positive biliary tract cancer (搜索) (BTC). The phase 2b study, led by researchers at The University of Texas MD Anderson Cancer Center, represents the largest HER2-targeted clinical database in BTC and directly supported the FDA's accelerated approval of zanidatamab in November 2024.
Trial Design and Patient Population
The HERIZON-BTC-01 trial enrolled 80 patients with previously treated, unresectable or metastatic biliary tract cancer (搜索) who had received gemcitabine chemotherapy and demonstrated HER2 (搜索) overexpression with an immunohistochemistry (IHC) score of 2+ or 3+. The patient population was 56% women with a median age of 64 years. Participants received zanidatamab 20 mg/kg every 2 weeks in 28-day cycles until discontinuation criteria were met, with 44.0% switching to another treatment after ending zanidatamab therapy.
Efficacy Outcomes
At a median follow-up of 33.4 months, zanidatamab demonstrated an objective response rate of 41.3% with a median duration of response of 14.9 months. The trial recorded three complete responses and 30 partial responses, while 22 patients had stable disease and 24 experienced progressive disease, resulting in a disease control rate of 69%. The median progression-free survival was 5.5 months, and overall survival reached 15.5 months.
Notably, two patients who were initially reported as having a partial response achieved a complete response by the final analysis, supporting continued benefit with zanidatamab therapy.
HER2 Expression Levels Drive Response
Patients with the strongest levels of HER2 (搜索) overexpression experienced significantly greater benefit from zanidatamab treatment. The 62 participants with IHC 3+ tumors achieved superior outcomes compared to the 18 patients with IHC 2+ for both confirmed objective response rate (51.6% vs 5.6%) and median overall survival duration (18.1 vs 5.2 months).
"Relative to IHC 3+ tumors, the more modest activity in IHC 2+/amplified tumors observed here supports reflex IHC testing and identifies a cohort for deeper investigation," the investigators noted.
Quality of Life Improvements
The trial demonstrated a correlation between zanidatamab response and improvement in pain levels, suggesting a potential positive impact on quality of life. Participants who experienced a complete or partial response had respective decreases of 4.0 points and 1.0 point on the Brief Pain Inventory-Short Form worst score (on a scale of 0-10 points, where 10 points equals worst pain imaginable), whereas those with progressive disease had an increase of 2.4 points.
In the cohort of 80 patients, those who responded to zanidatamab reported meaningful improvements in their symptoms, particularly in pain levels. Many experienced either reductions or stabilization of pain compared with their baseline, indicating the treatment not only controlled tumor growth but also helped alleviate disease-related discomfort.
Safety Profile
Zanidatamab demonstrated a manageable safety profile with no new safety concerns or treatment-related deaths reported. Diarrhea, decreased ejection fraction, and anemia were the only grade 3 treatment-related adverse events occurring in more than two patients (5.0%, 3.8%, and 3.8%, respectively). Only 3.0% of patients discontinued treatment due to side effects.
Clinical Significance and Future Directions
"The observed objective response rate, prolonged duration of response, and consistent activity in IHC3+ tumors underscores HER2 (搜索) as a valid therapeutic target in biliary tract cancer (搜索) and support the emerging role of zanidatamab in the treatment paradigm," said Shubham Pant, M.D., professor of Gastrointestinal Medical Oncology and Investigational Cancer Therapeutics at MD Anderson.
Zanidatamab is a bispecific antibody that binds to two distinct sites on the HER2 (搜索) receptor, enabling it to more effectively inhibit cancer cell growth and promote immune-mediated elimination of tumor cells compared with traditional HER2-targeted therapies.
The ongoing phase 3 HERIZON-BTC-302 trial is evaluating zanidatamab with standard-of-care first-line treatment in patients with HER2 (搜索)-positive (IHC 3+ or IHC 2+/amplified) BTC, potentially expanding its therapeutic application in this difficult-to-treat cancer population.