ABSTRACT NUMBER – 4008
A subset of biliary tract cancer cases presents either with overexpression or amplification of the HER2 gene. Zanidatamab, a bispecific antibody targeting two different epitopes of HER2, has shown acceptable tolerability and initial signs of anti-tumor activity in patients with treatment-resistant biliary tract cancer that expresses HER2 or exhibits amplification of the ERBB2 gene (also known as HER2). In late 2022, Zymeworks’ zanidatamab passed a critical clinical test, which paved the way for finalizing a licensing agreement with Jazz Pharmaceuticals. This agreement secured ample funding for the next phase of value generation for Zymeworks.
Jazz Pharmaceuticals and Zymeworks presented encouraging results from the Phase IIb HERIZON-BTC-01 trial (NCT04466891) of zanidatamab in patients with previously treated biliary tract cancers exhibiting HER2 amplification. The pivotal trial data, including new insights into progression-free survival (PFS), were highlighted in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The Lancet Oncology. Furthermore, the abstract (4008) was selected to be part of the esteemed 2023 Best of ASCO program scheduled for this summer after the ASCO Annual Meeting.
The trial evaluated zanidatamab, administered intravenously at a dose of 20 mg/kg every 2 weeks, in patients with locally advanced unresectable or metastatic biliary tract cancer (including gallbladder cancer and intra-/extra-hepatic cholangiocarcinoma) who had HER2 amplification and had previously received gemcitabine-containing therapy. Patients who had previously undergone HER2-targeted therapy were omitted. HER2 status was confirmed by a central laboratory using tissue samples. The study enrolled 87 patients, divided into two cohorts based on tumor immunohistochemistry (IHC) status. Cohort 1 included 80 patients with HER2-amplified tumors (IHC 2+/3+), while Cohort 2 consisted of 7 patients with non-amplified tumors (IHC 0/1+). Tumor response was assessed every 8 weeks based on RECIST v1.1 criteria. In Cohort 1, the confirmed objective response rate (cORR) was the main focus, evaluated by an independent central review (ICR). Additionally, secondary endpoints included measuring efficacy and safety outcomes.
In Cohort 1, the cORR was 41.3%, with a Kaplan Meier (KM) estimated duration of response (DOR) of 12.9 months according to ICR assessment and a median study follow-up time of 12.4 months. This response rate was more than double the historical rates of 5% to 15% reported for second-line standard-of-care chemotherapy in patients with biliary tract cancer. Additionally, new data presented at ASCO 2023 revealed a median progression-free survival (PFS) of 5.5 months in Cohort 1, surpassing the median PFS of 1.4 to 4 months typically achieved with current chemotherapy treatments for biliary tract cancer.
Out of the 33 patients who exhibited a positive response to the treatment as of the data cutoff on October 10, 2022, 16 patients (49%) were still experiencing ongoing responses, while 27 patients (81.8%) maintained a duration of response (DOR) of ≥16 weeks. The median time to the first confirmed response was 1.8 months.
Zanidatamab demonstrated a well-tolerated and manageable safety profile in the study, with only two out of the 87 patients (2.3%) discontinuing treatment due to adverse events (AEs). No severe Grade 4 AEs and no treatment-related deaths were reported. The most frequently observed AEs were diarrhea and infusion-related reactions, mostly mild in severity, reversible, and effectively managed through standard supportive care measures.
The findings from this study provide valuable evidence that zanidatamab offers significant clinical benefits and holds promise as a potential treatment option for HER2-positive biliary tract cancer. It is essential to note that the HERIZON-BTC-01 trial is ongoing, and certain secondary outcome measures, such as overall survival, have yet to mature.
