Jazz Pharmaceuticals plc and Zymeworks Inc. presented positive pivotal trial data, including new data on progression-free survival (PFS), from the Phase 2b HERIZON-BTC-01 trial of the bispecific antibody zanidatamab in previously treated HER2-amplified biliary tract cancers (BTC). The data were featured as an oral presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting, and the results were concurrently published in The Lancet Oncology. The abstract (4008) was also selected to be included in the 2023 Best of ASCO® program, which will be held this summer following the ASCO Annual Meeting.

For the trial's primary endpoint, data from 80 patients with HER2-amplified BTC (defined as in situ hybridization [ISH] positive and immunohistochemistry [IHC] 2+ or 3+) demonstrated a confirmed objective response rate (cORR) of 41.3% [95% confidence interval (CI): 30.4, 52.8] with a Kaplan Meier (KM) estimated median duration of response (DOR) of 12.9 months. The KM estimated median PFS was 5.5 months [95% CI: 3.7, 7.2] with a range of 0.3 to 18.5 months. Trial Results: Results of the pivotal HERIZON-BTC-01 trial (NCT04466891) indicate that the HER2-targeted, bispecific antibody zanidatamab demonstrates rapid, durable responses with a manageable safety profile in patients with treatment-refractory HER2-amplified BTC.

The trial evaluated zanidatamab (20 mg/kg IV every 2 weeks) in patients with HER2-amplified, locally advanced unresectable or metastatic BTC (gallbladder cancer, intra-/extra-hepatic cholangiocarcinoma) who had received prior gemcitabine-containing therapy. Patients with prior HER2-targeted therapy use were excluded from the trial. All patients were required to have HER2 status confirmed with tissue samples by a central lab.

Patients (n=87) were assigned into two cohorts based on tumor IHC status: Cohort 1 (n=80) included patients who were IHC 2+/3+ (HER2-amplified) and Cohort 2 (n=7) included patients who were IHC 0/1+. Tumors were assessed every 8 weeks per RECIST v1.1. The primary endpoint was cORR by independent central review (ICR) in Cohort 1, with secondary endpoints including other efficacy and safety outcomes. In Cohort 1, cORR was 41.3% [95% CI: 30.4, 52.8] with the KM estimated DOR of 12.9 months (range of 1.5 – 16.9+) by ICR assessment with a median study follow-up time of 12.4 months (range of 7 – 24).

The response was more than double the historical response rates of 5 to 15% reported for second-line standard of care chemotherapy in patients with BTC. The median PFS in Cohort 1, which is new data presented at ASCO 2023, was 5.5 months [95% CI: 3.7, 7.2], with a range of 0.3 to 18.5 months. Current chemotherapy treatments have shown to provide a median PFS of 1.4 - 4 months in patients with BTC.

Among the 33 responding patients at the data cutoff (October 10, 2022), 16 patients (49%) had ongoing responses and 27 patients (81.8%) had a DOR of =16 weeks. The median time to first confirmed response was 1.8 months (range, 1.6 – 5.5). No responses were observed in Cohort 2. Zanidatamab demonstrated a manageable and tolerable safety profile, with two of the 87 patients (2.3%) experiencing adverse events (AEs) leading to treatment discontinuation.

There were no Grade 4 AEs and no deaths were treatment-related. The most common AEs were diarrhea and infusion-related reactions, which were predominately low-grade, reversible and manageable with routine supportive care. The HERIZON-BTC-01 trial is ongoing and some secondary outcome measures, including overall survival, are not yet mature.