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    Zanidatamab: A New Frontier in Treating HER2-Positive Biliary Tract Cancer With James Harding, MD

    Expert Perspectives · Keira Smith · 2024-12-11

    The FDA’s recent accelerated approval of zanidatamab marks a significant breakthrough in the treatment landscape for human epidermal growth factor receptor 2 (HER2)–positive biliary tract cancer (BTC). Following the approval, Dr. James Harding, Associate Attending Physician in the Gastrointestinal Oncology and Early Drug Development Services at Memorial Sloan Kettering Cancer Center, sat down to provide oncology clinicians with insights into its significance and implications for clinical practice.

    The Challenge of Biliary Tract Cancers

    Biliary tract cancers, encompassing intrahepatic and extrahepatic cholangiocarcinoma, as well as gallbladder cancer, are uncommon yet aggressive malignancies. These cancers often present at advanced stages, rendering curative approaches, such as surgical resection, impractical. Despite recent advancements in systemic treatments like chemoimmunotherapy, patients with BTC continue to face poor outcomes, emphasizing the urgent need for novel therapies.

    Genomic profiling has revealed significant heterogeneity among BTC, with a subset of these cancers driven by HER2 overexpression. This discovery has opened new avenues for precision oncology. By targeting HER2, clinicians can potentially improve treatment outcomes for this subset of patients.

    Zanidatamab: HER2-Targeted Bispecific Antibody

    Zanidatamab is a novel bispecific antibody designed to bind two distinct epitopes on the HER2 protein, providing a multifaceted mechanism of action. In preclinical models, zanidatamab has demonstrated the ability to:

    1. Inhibit HER2 signaling pathways
    2. Induce HER2 receptor downregulation
    3. Elicit immune-mediated cytotoxicity against HER2-positive cancer cells

    This innovative approach enhances its efficacy compared to traditional HER2-targeted therapies. The HERIZON-BTC-01 trial has provided robust evidence supporting its clinical utility.

    Key Findings from the HERIZON-BTC-01 Trial

    HERIZON-BTC-01 trial was a global, open-label, phase 2 study evaluating zanidatamab in HER2-amplified BTC patients who had progressed on prior systemic therapy. The trial enrolled 87 patients, stratified into two cohorts:

    • Cohort 1 (80 patients): HER2-amplified with high HER2 overexpression (immunohistochemistry 2+ or 3+)
    • Cohort 2 (7 patients): HER2-amplified with low HER2 expression (IHC 0 or 1+)

    Patients received zanidatamab intravenously every two weeks, with a primary end point of objective response rate (ORR) by central review.

    Results:

    • Efficacy: In Cohort 1, zanidatamab achieved an ORR of approximately 40%, with some patients experiencing near-complete tumor regression. Median duration of response ranged from 12.9 to over 14 months
    • Enhanced outcomes: Patients with IHC 3+ tumors exhibited even higher response rates and improved survival metrics
    • Safety profile: Zanidatamab was well-tolerated, with manageable side effects including low-grade diarrhea and infusion-related reactions. These were effectively addressed with premedications

    These findings formed the basis for the FDA’s accelerated approval, highlighting zanidatamab as a promising second-line treatment for HER2-positive BTC.

    Clinical Implications

    The approval of zanidatamab introduces a new treatment option for HER2-positive BTC patients who have progressed on standard chemoimmunotherapy. Given its favorable safety profile and notable efficacy, it is poised to become a standard of care for this patient population.

    However, clinicians must ensure comprehensive molecular profiling, including HER2 IHC testing and next-generation sequencing, for all BTC patients to identify eligible candidates for zanidatamab. For patients with HER2 IHC 3+ tumors, zanidatamab offers a compelling option with a strong evidence base.

    Future Directions and Ongoing Research

    Building on the success of HERIZON-BTC-01, a confirmatory phase 3 trial is currently underway to evaluate zanidatamab in the frontline setting. This global randomized study compares standard gemcitabine-cisplatin (GemCis) plus immunotherapy with GemCis plus zanidatamab, aiming to improve progression-free survival.

    This trial represents a critical step toward integrating zanidatamab into earlier lines of therapy, potentially transforming the treatment paradigm for HER2-positive BTC. Clinicians are encouraged to support patient enrollment in this study to advance the field further.

    Conclusion

    Zanidatamab’s approval underscores the importance of precision medicine in oncology, providing a targeted and effective option for HER2-positive BTC patients. As the first FDA-approved therapy specifically for BTC, zanidatamab sets a precedent for future drug development in this challenging disease area.

    For oncology clinicians, the takeaway is clear: prioritize HER2 testing for BTC patients, consider zanidatamab as a second-line option for eligible patients, and support ongoing clinical trials to confirm and expand its use.

    For More Information

    About Dr. Harding

    James Harding, MD, is an Associate Attending Physician in the Gastrointestinal Oncology and Early Drug Development Services at Memorial Sloan Kettering Cancer Center. He specializes in the treatment of gastrointestinal, liver, and bile duct cancers.