Zanidatamab Plus Chemotherapy Shows Promising Anti-Tumor Activity in Treatment of HER2-Mutated Breast Cancer

Zanidatamab (Ziihera; Jazz Pharmaceuticals, Inc) plus chemotherapy demonstrated a manageable safety profile with promising antitumor activity and durable responses in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-mutated metastatic breast cancer (mBC). The data were presented at the European Society for Medical Oncology Breast Cancer 2025 Annual Meeting in Berlin, Germany.

3D rendering of bispecific antibodies in action | Image Credit: © Александр Михайлюк - stock.adobe.com

HER2 mutations are the most common mutations in BC, accounting for approximately 70% of all diagnoses. Despite continued advancements in therapeutic options that overcome poor prognoses and complications such as treatment resistance, challenges remain.¹

Zanidatamab is a HER2-targeting bispecific antibody that was initially approved by the FDA in 2024 for the treatment of patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer. Zanidatamab binds to 2 sites on HER2 proteins, and once internalized, reduces the number of proteins on the surface of the BC cell. The agent can additionally engage the immune system to attack the tumor cells.^2,3

Considering the success of zanidatamab in the treatment of HER2-mutated tumors, investigators conducted a trial (NCT02892123) evaluating its potential use as a treatment for HER2-mutated BCs. The trial is divided into 3 parts, of which part 1 evaluated dosage; part 2 assessed the safety, tolerability, and efficacy of zanidatamab as a monotherapy; and part 3 evaluated the safety, tolerability, and efficacy of zanidatamab in combination with chemotherapy (paclitaxel [Taxol; Bristol Myers Squibb], capecitabine [Xeloda; Genetech, Roche], or vinorelbine [Navelbine; Pierre Fabre]).^4-6

The trial assessed a total of 46 patients with HER2-positive (HER2+; n = 31) or HER2-low mBC (n = 15) who were previously treated with either trastuzumab (93%; Herceptin; Genentech, Roche), trastuzumab emtansine (91%; Kadcyla; Genentech, Roche), pertuzumab (80%; Perjeta; Genentech, Roche), lapatinib (24%; Tykerb; Novartis), trastuzumab deruxtecan (9%; Enhertu; Daiichi Sankyo, AstraZeneca), tucatinib (9%; Tukysa®; Seagen, Pfizer), or neratinib (7%; Nerlynx; Puma Biotechnology). Patients with HER2-low mBC required greater than or equal to 1 and less than or equal to 3 prior systemic chemotherapy regimens. The primary end point was safety and tolerability, with key secondary end points including objective response rate (ORR) and progression-free survival (PFS).^4,5

Of the trial population, 5 patients were treated with zanidatamab plus paclitaxel, 19 with zanidatamab plus capecitabine, 20 with zanidatamab plus vinorelbine, and 2 with zanidatamab plus tucatinib. At the median follow-up duration of 6 months (range: 2–63 months; data cut-off: 30 September 2024). Overall, zanidatamab plus chemotherapy were well tolerated, with 61% of patients experiencing grade 3 or 4 adverse events (AEs), of which diarrhea (7%), neutropenia (9%), and a reduced neutrophil count (24%) were the most common. Only 4% of patients stopped therapy, and there were no grade 5 incidents.^4,5

Both HER2-positive and HER2-low populations exhibited promising clinical activity. The median duration of response (DoR) and PFS among HER2-positive patients (n = 28) were 14.8 and 10.4 months, respectively, with a confirmed objective response rate (cORR) of 43%. The median DoR was 10.4 months, the median PFS was 3.7 months, and the cORR was 20% in the HER2-low group (n = 15).^4,5

These findings support zanidatamab as a promising treatment option for patients with HER2-mutated metastatic breast cancer, particularly those who have exhausted multiple prior lines of HER2-targeted therapy. As HER2 mutations continue to represent a significant subset of BC diagnoses, zanidatamab's clinical activity in heavily pretreated patients warrants further investigation to better define its role in the evolving treatment landscape.

REFERENCES

1. Cancer stat facts: Female breast cancer subtypes. National Cancer Institute. Accessed May 21, 2025. https://seer.cancer.gov/statfacts/html/breast-subtypes.html

2. FDA grants accelerated approval to zanidatamab-hrii for previously treated unresectable or metastatic HER2-positive biliary tract cancer. FDA. November 20, 2024. Accessed May 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanidatamab-hrii-previously-treated-unresectable-or-metastatic-her2

3. Ziihera: A dual her2-targeted treatment for HER2-positive BTC. Ziihera. Accessed May 21, 2025. https://www.ziihera.com/

4. Trial of ZW25 (zanidatamab) in patients with advanced HER2-expressing cancers. Updated November 27, 2024. Accessed May 21, 2025. https://clinicaltrials.gov/study/NCT02892123

5. Bedard P.L., Im S-A., Elimova E, et al. 303MO Zanidatamab (Zani) + chemotherapy (Chemo) for patients (Pts) with HER2-expressing metastatic breast cancer (mBC): Final results of a phase I trial. ESMO Open. May 2025. doi: 10.1016/j.esmoop.2025.104875

6. Zanidatamab Plus Chemo Shows Response in HER2+ and HER2-Low mBC. Docwire News. May 16, 2025. Accessed May 21, 2025. https://www.docwirenews.com/post/zanidatamab-plus-chemo-shows-response-in-her2-and-her2-low-mbc