Positive Results of HERIZON-BTC-01 study Evaluating Zanidatamab

HERIZON-BTC-01 study findings

A subset of biliary tract cancer cases presents with either overexpression or amplification of the HER2 gene. Zanidatamab, a bispecific antibody that targets two different HER2 epitopes, demonstrated 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). Zymeworks' zanidatamab successfully passed the clinical key test in late 2022. This achievement paved the way for the finalization of a licensing agreement with Jazz Pharmaceuticals, securing ample funding for the next phase of value generation for Zymeworks. 

Jazz Pharmaceuticals and Zymeworks jointly 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 through an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. The findings were also simultaneously published in The Lancet Oncology. Moreover, the abstract (4008) was chosen to be part of the esteemed 2023 Best of ASCO program, scheduled to take place this summer after the ASCO Annual Meeting.

The trial assessed zanidatamab, given intravenously at a dose of 20 mg/kg every 2 weeks, in patients with locally advanced unresectable or metastatic BTC (gallbladder cancer, intra-/extra-hepatic cholangiocarcinoma) who had HER2 amplification and had previously received gemcitabine-containing therapy. Patients who had received prior HER2-targeted therapy were excluded. HER2 status was confirmed by a central laboratory using tissue samples. The study included 87 patients, divided into two cohorts based on tumor immunohistochemistry (IHC) status. Cohort 1 (80 patients) had HER2-amplified tumors (IHC 2+/3+), while Cohort 2 (7 patients) had non-amplified tumors (IHC 0/1+). Tumor response was assessed every 8 weeks according to RECIST v1.1 criteria. The primary endpoint was the confirmed objective response rate (cORR) assessed by an independent central review (ICR) in Cohort 1, with secondary endpoints focusing on efficacy and safety outcomes.

In Cohort 1, cORR was 41.3% with the Kaplan Meier (KM) estimated DOR of 12.9 months by ICR assessment with a median study follow-up time of 12.4 months. 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 new data presented at ASCO 2023 also 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 BTC.

Out of the 33 patients who exhibited a positive response to the treatment at the data cutoff on October 10, 2022, 16 patients (49%) were still experiencing ongoing responses, while 27 patients (81.8%) maintained a DOR of ≥16 weeks. The median time it took for the first confirmed response to occur was 1.8 months.



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


Time to First Response

Median months: 1.8 (1.6 – 5.5)

Zanidatamab exhibited 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). There were no severe Grade 4 AEs, and no deaths were attributed to the treatment. The most frequently observed AEs were diarrhea and infusion-related reactions, which were 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 BTC. It is important to note that the HERIZON-BTC-01 trial is still ongoing, and certain secondary outcome measures, such as overall survival, have not yet matured.

KOL insights

“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” –Expert Opinion.

“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”–Expert Opinion.


According to the American Cancer Society, in the United States, about 8,000 new cases of BTC are diagnosed each year. However, as these malignancies can be challenging to identify and are frequently misclassified, hence the real numbers could be higher. HER2 is overexpressed or amplified in a subset of BTC. A HER2-targeted therapy has not yet been authorized for the treatment of BTC, and about 5% to 19% of BTC patients have tumors that express HER2 and may be candidates for this HER2-targeted treatment.  After receiving first-line therapy, patients with locally advanced/metastatic BTC who continue to progress are treated with standard treatment, which has limited clinical benefit with modest improvement in survival. Gastric and breast cancer survival has increased with HER2-targeted therapy. The results from the pivotal HERIZON-BTC-01 trial reveal that zanidatamab shows prompt and long-lasting responses while maintaining a tolerable safety profile, in patients with HER2-amplified BTC who have not responded to previous treatments. Clinical studies are also being conducted to examine the therapeutic potential of zanidatamab both alone and in combination with first-line chemotherapy for HER2-positive BTC.

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