Pharmacy Practice in Focus: Oncology
The FDA approves zanidatamab for HER2-positive biliary cancer, improving treatment options.
The recent FDA approval of zanidatamab-hrii (Ziihera; Jazz Pharmaceuticals) marks a pivotal moment in the treatment of unresectable or metastatic HER2-positive (HER2+) biliary tract cancer (BTC). With its dual HER2-targeting mechanism, zanidatamab has demonstrated significant clinical efficacy and a favorable safety profile, offering new hope for patients with limited treatment options.
Zanidatamab was granted accelerated FDA approval on November 24, 2024, for the treatment of adult patients with previously treated, unresectable locally advanced or metastatic HER2+ (immunohistochemistry [IHC] 3+) BTC as detected by an FDA-approved test, based on findings from the HERIZON-BTC-01 clinical trial (NCT04466891).1 This approval underscores its potential as a transformative therapy in an area of high unmet need.
BTCs, comprising cholangiocarcinoma and gallbladder cancer, are rare but aggressive malignancies, accounting for approximately 3% of gastrointestinal cancers. Approximately 30% to 40% of BTC cases harbor actionable genomic alterations, with HER2 alterations accounting for 20%.2 This highlights HER2 as a clinically relevant target for therapeutic intervention, as seen with zanidatamab. Historically, HER2+ BTC has been associated with poor prognosis and limited treatment options.3 However, the emergence of HER2-targeted therapies, such as zanidatamab, offers new hope for this distinct molecular subset of patients.
In the first-line setting, per National Comprehensive Cancer Network (NCCN) guidelines, patients are typically treated with palliative gemcitabine-cisplatin (GemCis) or GemCis plus immune checkpoint inhibitors, such as durvalumab (Imfinzi; AstraZeneca) or pembrolizumab (Keytruda; Merck & Co). The addition of durvalumab to GemCis has shown a median overall survival (OS) of 12.8 months, an improvement over GemCis alone (11.7 months).4 However, subsequent lines of cytotoxic therapy yielded a median OS of only 6.2 to 8.6 months, with treatment responses in less than 15% of patients.4 This underscores the need for additional treatment options in BTC.
Zanidatamab’s novel mechanism of action and robust clinical trial results provide a promising avenue for improving outcomes in this challenging malignancy.1,5 Its approval represents a key step forward in addressing the limited therapeutic options available for patients with HER2+ BTC, potentially offering improved survival and quality of life for those facing this aggressive form of cancer.
Zanidatamab is a dual HER2-targeted bispecific antibody designed to bind simultaneously to 2 distinct epitopes of the HER2 receptor (biparatopic), thereby enhancing its antitumor activity. Unlike traditional HER2-targeted therapies, such as trastuzumab (Herceptin; Roche) or pertuzumab (Perjeta; Genentech), zanidatamab’s dual binding results in more-effective receptor clustering, internalization, and degradation.6 Additionally, its biparatopic binding leads to the removal of HER2 protein from the cell surface, further contributing to its enhanced antitumor activity.4,6 The unique mechanism of zanidatamab also facilitates immune-mediated mechanisms, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, while inhibiting HER2 and HER3 signaling pathways critical for tumor growth and survival.6 Importantly, zanidatamab demonstrates a potent induction of complement-dependent cytotoxicity, which distinguishes it from other HER2-targeted agents such as trastuzumab or pertuzumab.6
In addition, as a bispecific antibody, zanidatamab has a differentiated and established clinical profile, providing a chemotherapy-free option for patients. Its mechanism circumvents common resistance mechanisms seen with single-epitope HER2 therapies, making it a valuable option for heavily pretreated patients. This innovative approach aligns with the evolving paradigm of precision oncology, where treatments are tailored to specific molecular targets within tumors.5
The accelerated approval of zanidatamab is based on the robust results from HERIZON-BTC-01, a global, multicenter, single-arm, phase 2b trial that evaluated its efficacy in HER2+ (IHC 3+) patients with BTC (n = 62) and assessed safety in cohort 1 (n = 80). The trial enrolled 87 patients with HER2-amplified, unresectable, locally advanced or metastatic BTC who had experienced progression on previous gemcitabine-based therapy. For clarity, the primary efficacy analysis was conducted for cohort 1.7
Key findings from the trial include the following:
These outcomes demonstrate zanidatamab’s substantial antitumor activity and its potential to redefine treatment standards for HER2+ BTC.
The safety profile of zanidatamab, as established in the HERIZON-BTC-01 trial involving both cohort 1 and cohort 2 with a total of 87 patients, demonstrates a manageable and generally favorable tolerability. Serious treatment-related adverse events (TRAEs) were reported in 8 patients (9.2%), according to the latest data cutoff in July 2023.8 Grade 3 or 4 TRAEs occurred in 20.7% of patients. Per the latest data cutoff, there was 1 grade 4 event of increased aspartate aminotransferase level, and no grade 5 events were reported.8 This absence of severe toxicities underscores zanidatamab’s favorable safety profile.
The most common AEs, occurring in at least 20% of patients, were diarrhea, infusion-related reactions (IRRs), abdominal pain, and fatigue.7 Diarrhea was the most frequently reported TRAE, affecting 36.8% of patients. Importantly, the majority of diarrhea cases (84%) were grade 1 or 2, and all but 2 grade 3 events were successfully managed in the outpatient setting, typically with loperamide.7 This suggests that diarrhea, although common, is generally mild and manageable with appropriate interventions. IRRs were the second most common TRAE, occurring in 33% of patients.7 The study findings did not report severe complications from these reactions, indicating they were generally manageable. Per prescribing information, premedication with acetaminophen, an antihistamine, and a corticosteroid 30 to 60 minutes prior to each zanidatamab infusion is recommended to help prevent potential IRRs.1
Beyond these common AEs, there is a risk of left ventricular ejection fraction (LVEF) decrease with zanidatamab. Harding et al reported that ejection fraction decreases were observed in 5 patients (6%), who all had clinically asymptomatic cardiac events that were confounded by preexisting or concurrent conditions.
The overall safety data from the HERIZON-BTC-01 trial suggest that zanidatamab is well tolerated, with most AEs being manageable and a low treatment discontinuation rate of 2.3%.8 This safety profile, combined with its efficacy, positions zanidatamab as a promising treatment option for patients with HER2+ BTC.
Although chemotherapy regimens such as gemcitabine and cisplatin remain the standard first-line treatment for BTC, their effectiveness diminishes in subsequent lines of therapy, where FOLFOX (folinic acid, fluorouracil, and oxaliplatin) is the preferred regimen according to NCCN guidelines. This highlights the need for novel therapeutic approaches.
The accelerated approval of zanidatamab provides a breakthrough for patients with HER2+ BTC, addressing a critical gap in care. By achieving meaningful responses in patients with prior treatment (median line of therapy, 1), zanidatamab represents a transformative advancement and promising new standard for managing this aggressive disease.
Pharmacists and health care providers play a pivotal role in the successful integration of zanidatamab into clinical practice. Key responsibilities include:
As zanidatamab is a newly approved therapy, its accessibility will depend on multiple factors, including cost, insurance coverage, and health care infrastructure. Although its potential to improve outcomes for patients with HER2+ BTC is significant, health care systems must carefully balance these benefits against the financial burden associated with treatment. The FDA’s accelerated approval and designation of zanidatamab as a breakthrough therapy further highlight its importance in addressing an unmet medical need.
Zanidatamab is administered as an intravenous infusion of 20 mg/kg every 2 weeks until disease progression or unacceptable toxicity occurs, requiring significant health care resources.1 Institutions must establish protocols for safe and efficient drug administration while proactively managing potential AEs, such as IRRs and diarrhea, to ensure patient adherence and treatment success.
Ongoing research and postmarketing surveillance will provide valuable insights into zanidatamab’s long-term safety and efficacy. The phase 3 HERIZON-BTC-302 confirmatory trial is currently evaluating zanidatamab in combination with standard-of-care therapy vs standard-of-care therapy alone in the first-line setting for patients with HER2+ BTC.9 This study could potentially expand zanidatamab’s use to earlier lines of treatment.
Additionally, zanidatamab is being investigated in other HER2+ malignancies. The HERIZON-GEA-01 (NCT05152147) trial is assessing zanidatamab plus chemotherapy with or without tislelizumab (Tevimbra; BeiGene) as first-line treatment for advanced/metastatic HER2+ gastroesophageal adenocarcinomas.9 The phase 3 EmpowHER-303 trial (NCT06435429) is evaluating zanidatamab in combination with chemotherapy for HER2+ metastatic breast cancer in patients who have experienced progression on or have intolerance to trastuzumab deruxtecan (Enhertu; Daiichi Sankyo and AstraZeneca).9 Furthermore, the DiscovHER PAN-206 study (NCT06695845) is a phase 2 trial evaluating zanidatamab in patients with previously treated HER2-expressing solid tumors. As the oncology landscape continues to evolve, zanidatamab represents a significant step forward in the pursuit of precision medicine for HER2+ cancers beyond biliary tract malignancies.
Amir Ali, PharmD, BCOP, is a clinical pharmacist specialist at the University of Southern California (USC) Norris Comprehensive Cancer Center and an adjunct assistant professor of pharmacy practice at USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
Teny Khachadourian is a class of 2025 PharmD candidate at the University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
The accelerated approval of zanidatamab marks a significant advancement in the treatment of patients with HER2+ BTC. As the first HER2-targeted bispecific antibody approved for this indication in the US, it addresses a critical unmet need. The impressive clinical trial results, including a 41.3% confirmed ORR and a median DOR of 14.9 months, underscore its potential to improve outcomes in this challenging malignancy.8
For patients and health care providers, zanidatamab offers renewed hope, particularly for those with HER2 IHC 3+ tumors, where a median OS of 18.1 months and an ORR of 52% were observed.8 By staying informed about the latest advancements and fostering interdisciplinary collaboration, pharmacists and oncologists can ensure the successful integration of zanidatamab into clinical practice while carefully managing its safety profile. As we embrace this innovative therapy, we not only improve current treatment options but also pave the way for further research and development in targeted therapies for BTCs.
