On June 1, 2024 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported long-term follow-up results, including the first-ever overall survival (OS) findings, from the Phase 2b HERIZON-BTC-01 clinical trial of zanidatamab in previously treated, unresectable, locally advanced, or metastatic HER2-positive biliary tract cancer (BTC) (Press release, Jazz Pharmaceuticals, JUN 1, 2024, View Source [SID1234643956]). These data will be featured at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in a poster presentation during the Gastrointestinal Cancer – Gastroesophageal, Pancreatic, and Hepatobiliary session on June 1, 2024, at 1:30-4:30 p.m. CDT. Zanidatamab is a human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody being studied in multiple solid tumors.
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For the trial’s primary endpoint, results demonstrated that a confirmed objective response rate (cORR) by independent central review (ICR) was maintained at 41.3% (95% confidence interval (CI): 30.4, 52.8) and one additional patient achieved a complete response (n=2; 2.5%) since initial findings were presented at the ASCO (Free ASCO Whitepaper) Annual Meeting in 2023. The median duration of response (DoR), one of the trial’s key secondary endpoints, increased by approximately 2 months to 14.9 months (95% CI: 7.4, not reached), compared to the previously reported findings. In this data cut, zanidatamab demonstrated a median estimated OS, another secondary endpoint, of 15.5 months (95% CI: 10.4, 18.5) in all patients with HER2+ BTC, 18.1 months (95% CI:12.2, 23.2) in patients with IHC 3+ tumors, and 5.2 months (95% CI: 3.1, 10.2) in patients with IHC 2+ tumors. Results highlight the clinically meaningful benefits of sustained and durable responses with continued treatment with zanidatamab.
"Patients with BTC are typically diagnosed when their disease is at an advanced stage, which is associated with a poor prognosis," said Shubham Pant, M.D., M.B.B.S. professor in the Department of Gastrointestinal Medical Oncology and Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. "Historically, overall survival with standard-of-care chemotherapy in second-line patients with advanced BTC is reported to be between 6-9 months1 so there is a significant unmet need for targeted therapies that can potentially improve survival. The deep and durable responses seen in this study signal the potential to fill a critical unmet patient need with zanidatamab, a chemotherapy-free option, among patients with HER2-expressing cancers."
"We are encouraged by the updated results from the pivotal HERIZON-BTC-01 trial demonstrating sustained clinical activity in previously treated patients with advanced HER2-positive BTC. Results from HERIZON-BTC-01 were included in the Biologics License Application (BLA) for zanidatamab, which was granted Priority Review by the FDA earlier this week, as well as in the Marketing Authorization Application for zanidatamab which was recently submitted to the European Medicines Agency," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "Clinical development of zanidatamab for the treatment of advanced HER2-positive BTC continues with HERIZON-BTC-302 (NCT06282575), the ongoing, global, randomized Phase 3 trial of zanidatamab in combination with standard-of-care therapy in the first-line setting for patients with HER2-positive BTC. We also look forward to investigating zanidatamab’s potential in other HER2-expressing solid tumors, including in cases resistant to prior HER2-targeted therapies."
Trial Results
Results from this long-term analysis of the Phase 2b HERIZON-BTC-01 trial (NCT04466891) indicate that zanidatamab monotherapy demonstrated sustained and durable antitumor responses in previously treated patients with HER2-positive unresectable, locally advanced, or metastatic BTC and support the clinically meaningful benefit of continued treatment with zanidatamab. The safety profile in all enrolled patients remained manageable with favorable tolerability compared with the initial analysis. Two (2.3%) patients discontinued treatment due to treatment-related adverse events (TRAEs).
The trial evaluated zanidatamab (20 mg/kg IV once every 2 weeks) in patients with HER2-positive, locally advanced unresectable, or metastatic BTC 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 centrally confirmed HER2-amplified tumors (assessed by in situ hybridization). 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-positive) and Cohort 2 (n=7) included patients who were IHC 0/1+. The median duration of follow-up was 21.9 (16-34) months. Tumors were assessed every 8 weeks per RECIST v1.1. Updated efficacy analyses include only Cohort 1, while safety analyses include Cohorts 1 and 2.
As of July 28, 2023, data from HER2-positive BTC patients enrolled in Cohort 1 (n=80) demonstrated:
With longer follow-up, the cORR was maintained from the initial analysis (n=33; 41.3%) (95% CI: 30.4, 52.8), with one additional complete response (n=2; 2.5%).
Although the trial was not designed to detect treatment effects by HER2 status, as previously reported, in a pre-planned subgroup analysis of cORR by HER2 expression, responses were observed in patients with IHC 3+ tumors (cORR: 51.6% [95% CI: 38.6%-64.5%]) and IHC 2+ tumors (cORR: 5.6% [95% CI: 0.1-27.3%])2.
A two-month increase in the median DoR to 14.9 months (95% CI: 7.4, not reached).
In patients with IHC3+ tumors, the median DoR was 14.9 months (95% CI: 7.4, not reached).
The DOR in the 1 responder with IHC 2+ tumors was 7.5 months.
A median OS (95% CI) of 15.5 months (95% CI: 10.4, 18.5).
The median OS in patients with IHC 3+ was 18.1 months (95% CI: 12.2, 23.2).
The median OS in patients with IHC 2+ was 5.2 months (95% CI: 3.1, 10.2).
Median progression-free survival (PFS) was maintained (5.5 months [95% CI: 3.6, 7.3]) compared with the initial analysis, which had a data cutoff of October 10, 2022.
In patients with IHC 3+ tumors, the median PFS was 7.2 months (95% CI: 5.4, 9.4) months.
In patients with IHC 2+ tumors, the median PFS was 1.7 months (95% CI: 1.0, 3.3) months.
As previously reported for Cohorts 1 and 2, zanidatamab demonstrated a manageable and tolerable safety profile, with no new safety signals identified and no deaths that were treatment related. TRAEs leading to dose reductions remained infrequent. Serious TRAEs occurred in eight (9.2%) patients. One patient experienced serious TRAEs since the initial analysis (alanine aminotransferase increased and aspartate aminotransferase increased).Treatment discontinuation rate was 2.3% and no additional patients discontinued treatment due to TRAEs since the initial analysis.
About BTC
BTC, including gallbladder cancer and intrahepatic and extrahepatic cholangiocarcinoma, account for <1% of all adult cancers globally and are often associated with a poor prognosis.3,4 The human epidermal growth factor receptor 2 (HER2) is a well-validated target for antitumor therapy in other cancers. Across the U.S., Europe, and Japan, approximately 12,000 people are diagnosed with HER2+ BTC annually.5,6,7,8
About Zanidatamab
Zanidatamab is an investigational HER2-targeted bispecific antibody that can simultaneously bind two non-overlapping epitopes of the HER2 receptor, known as biparatopic binding. This unique design and increased binding results in multiple mechanisms of action, including dual HER2 signal blockade, removal of HER2 protein from the cell surface, and immune-mediated cytotoxicity leading to encouraging antitumor activity in patients. Zanidatamab is being developed in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. Zanidatamab is being developed by Jazz and BeiGene, Ltd. (BeiGene) under license agreements from Zymeworks, which first developed the molecule.
The U.S. Food and Drug Administration (FDA) has accepted and granted Priority Review of the Biologics License Application (BLA) for zanidatamab with a Prescription Drug User Fee Act (PDUFA) action date of November 29, 2024. Zanidatamab was also granted Breakthrough Therapy designation in patients with previously treated HER2 gene-amplified biliary tract cancers (BTC) and given two Fast Track designations: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for 1L gastroesophageal adenocarcinoma (GEA). Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of BTC and gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China.