On June 2, 2023 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) and Zymeworks Inc. (Nasdaq: ZYME) reported 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) (Press release, Jazz Pharmaceuticals, JUN 2, 2023, View Source [SID1234632404]). The data were featured as an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 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 (Free ASCO Whitepaper) program, which will be held this summer following the ASCO (Free ASCO Whitepaper) Annual Meeting.
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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.
"With a confirmed ORR of 41.3 percent, median DOR of 12.9 months and median PFS of 5.5 months, these results for zanidatamab are a significant step forward for second-line treatment of HER2-amplified BTC, where current chemotherapy treatments have been reported to provide only a 5 to 15 percent ORR and median PFS of 1.4 to 4 months," said Shubham Pant, M.D., professor of Gastrointestinal Medical Oncology and Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. "The HERIZON-BTC-01 trial advances an exciting field of oncology research where we can leverage next-generation sequencing on BTC patients to understand genomic markers of the disease and choose the appropriate targeted therapies for these patients."
"We are thrilled to deliver an oral presentation on the pivotal HERIZON-BTC-01 study results demonstrating zanidatamab’s meaningful clinical benefit and tolerable safety profile in patients with HER2-amplified BTC," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "We are committed to advancing this program as rapidly as possible to potentially transform the lives of patients in critical need, with the goal of delivering a chemotherapy-free option that is the first-and-only therapy that targets HER2-amplified BTC."
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%1,2 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 (Free ASCO Whitepaper) 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.1,2
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).
Cohort 1 (n=80)
Confirmed Objective Response Rate, % (95% CI)
41.3 (30.4, 52.8)
Confirmed Best Objective
Response, n (%)
Complete Response
1 (1.3)
Partial Response
32 (40)
Stable Disease
22 (27.5)
Progressive Disease
24 (30)
Disease Control Rate, (95%, CI)
68.8 (57.4, 78.7)
Progression Free Survival
Median months: 5.5 (0.3 – 18.5)
Duration of Response Greater than, or Equal to, 16
Weeks
27
Time to First Response
Median months: 1.8 (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.
The abstract is available to conference registrants on the ASCO (Free ASCO Whitepaper) conference website here. (Abstract Number 4008).
Webcast Information
Jazz Pharmaceuticals will host a webcast today, Friday, June 2, 2023, at 6:45 p.m. CT / 7:45 p.m. ET / 12:45 a.m. IST (June 3) to provide a review of the zanidatamab BTC data presented at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting. Dr. Shubham Pant, M.D., who is presenting the zanidatamab BTC findings at ASCO (Free ASCO Whitepaper), will provide an overview of the data. Dr. Pant is a professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.
Interested parties may register for the call in advance here or via the Investors section of the Jazz website at www.jazzpharmaceuticals.com. To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast.
A replay of the webcast will be available via the Investors section of the Jazz website at www.jazzpharmaceuticals.com.
About Zanidatamab
Zanidatamab is an investigational bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks, along with collaborators Jazz and BeiGene, Ltd. (BeiGene), are developing zanidatamab in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2.
The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified biliary tract cancers (BTC), and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for first-line 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 gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China.
About Biliary Tract Cancers
Biliary tract cancers (BTC), including gallbladder cancer and cholangiocarcinoma, account for approximately <1% of all adult cancers and are often associated with a poor prognosis.3,4 Globally, more than 210,000 people are diagnosed with BTC every year5 and most patients (> 65%) are diagnosed with tumors that cannot be removed surgically. The human epidermal growth factor receptor 2 (HER2) is a well-validated target for anti-tumor therapy in other cancers. About 5% to 19% of patients with BTC have tumors that express HER26 and may be positioned for potential benefit from HER2-targeted therapy. Currently no HER2-targeted therapy has been approved for the treatment of BTC.