The HER2-targeting bispecific antibody zanidatamab generated rapid and durable responses in patients with HER2-amplified, locally advanced, unresectable or metastatic biliary tract cancer previously treated with gemcitabine, investigators from the global phase IIb HERIZON-BTC-01 study reported at the 2023 ASCO Annual Meeting.1 The findings were simultaneously published in The Lancet Oncology.2
HER2 is overexpressed or amplified in a subset of biliary tract cancer, and zanidatamab simultaneously targets two distinct HER2 epitopes. “The unique binding properties of zanidatamab to HER2 result in multiple mechanisms of action, and preclinical studies demonstrate greater activity for this drug than trastuzumab with or without pertuzumab,” said Shubham Pant, MD, of The University of Texas MD Anderson Cancer Center, Houston.
Shubham Pant, MD
In the study, the confirmed objective response rate by independent central review was 41.3% in cohort 1, which comprised patients with an immunohistochemistry (IHC) score of 2+ or 3+. The median duration of response with zanidatamab was 12.9 months after a median follow-up of 12.4 months.
The study enrolled 87 patients who had experienced disease progression on an average of one prior gemcitabine-based regimen and were naive to anti-HER2 agents. Their cancers were gallbladder cancer (51%), intrahepatic cholangiocarcinoma (29%), and extrahepatic cholangiocarcinoma (20%). All but seven patients had IHC 2+ or 3+ expression (cohort 1). A second small cohort comprised seven patients with IHC 1+ or 0 (cohort 2). Patients were treated with zanidatamab at 20 mg/kg on days 1 and 15 of each 28-day cycle. The primary endpoint was confirmed objective response rate.
Confirmed partial responses were observed in 40.0%, complete responses were reported in 1.3%, and stable disease was found in 27.5%, yielding a disease control rate of 68.8% in cohort 1 patients with HER2 IHC 2+ or 3+. Cohort 2 did not respond to zanidatamab. Median time to response in cohort 1 was 1.8 months, and 68.4% had a decrease in target lesions. Median progression-free survival in cohort 1 was 5.5 months.
Serious adverse events occurred in 8.8% of patients; none were grade 4 or 5. Diarrhea was the most common toxicity with zanidatamab, which was predominantly low grade and manageable. Few patients discontinued treatment because of toxicity.
“Most subtypes of biliary tract cancer seemed to benefit from the treatment,” Dr. Pant said. “These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer.”
Additional studies are ongoing or planned. The use of zanidatamab combined with gemcitabine/cisplatin will also be evaluated.
DISCLOSURE: Dr. Pant has served as a consultant or advisor to Ipsen, Janssen, Novartis, Zymeworks, AskGene, BPGBio, and Jazz Pharmaceuticals.
1. Pant S, Fan J, Oh DY, et al: Results from the pivotal phase 2b HERIZON-BTC-01 study: Zanidatamab in previously treated HER2-amplified biliary tract cancer. 2023 ASCO Annual Meeting. Abstract 4008. Presented June 2, 2023.
2. Harding JJ, Fan J, Oh DY, et al: Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): A multicentre, single-arm, phase 2b study. Lancet Oncol 24:772-782, 2023.