Zanidatamab/Chemotherapy Yields Responses and Is Safe in HER2-Expressing Metastatic Breast Cancer

Zanidatamab/Chemotherapy in HER2-Expressing

Metastatic Breast Cancer | Image Credit:

© Sebastian Kaulitzki – stock.adobe.com

The addition of zanidatamab (Ziihera) to chemotherapy demonstrated a manageable safety profile and preliminary antitumor activity in heavily pretreated patients with HER2-positive and HER2-low metastatic breast cancer, according to final results from part 3 of a phase 1 trial (NCT02892123) presented at the 2025 ESMO Breast Congress.1

Regarding safety, in the overall study population (n = 46), any-grade treatment-related adverse effects (TRAEs) occurred in 98% of patients, 46% of patients had grade 3/4 TRAEs, and serious TRAEs occurred in 2% of patients. Of note, no grade 5 TRAEs were observed. Notably, TRAEs leading to treatment discontinuation occurred in 4% (n = 2) of patients due to grade 2 abdominal pain and nausea (n = 1) and grade 3 diarrhea (n = 1); all TRAEs resolved following discontinuation. Grade 3/4 TRAEs that occurred in more than 2 patients included neutropenia/decreased neutrophil counts (30%) and diarrhea (7%). Grade 1/2 TRAEs that occurred in greater than 30% of patients included diarrhea (74%), nausea (48%), and stomatitis (33%).

In patients with HER2-positive metastatic breast cancer who had previously received HER2-targeted therapy (n = 28)—including trastuzumab (Herceptin), pertuzumab (Perjeta), and trastuzumab emtansine (T-DM1; Kadcyla)—the confirmed objective response rate (cORR) was 43% (95% CI, 24%-63%). In patients with HER2-low metastatic disease (n = 15), the cORR was 20% (95% CI, 4%-48%). Of note, 43% of patients with HER2-positive disease achieved a partial response (PR); no complete responses (CRs) were reported in this cohort. In the HER2-low cohort, 7% of patients achieved a CR, and 13% of patients achieved a PR.

“There’s an unmet clinical need for effective HER2-targeted therapies for patients whose disease has already progressed on prior HER2-targeted therapies,” Erika P. Hamilton, MD, a medical oncologist and director of the breast and gynecology research program at Sarah Cannon Research Institute in Nashville, Tennessee, stated in a presentation of the data.

Trial Design and Patient Characteristics

Zanidatamab is a dual HER2-targeted bispecific antibody that binds to 2 non-overlapping HER2 molecules in trans and has multiple mechanisms of action.2

The present phase 1 study evaluated zanidatamab plus chemotherapy in patients with unresectable, locally advanced or metastatic HER2-expressing breast cancer with an ECOG performance status of 0 or 1.1 Patients with stable brain metastases were allowed on the study. The HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/fluorescence in situ hybridization [FISH]–positive) cohort enrolled patients who were previously treated with trastuzumab, pertuzumab, or T-DM1 and had received 1 to 3 prior lines of chemotherapy. Those in the HER2-low (IHC 1+ or IHC 2+/FISH-negative) cohort had received 1 to 3 prior lines of chemotherapy.

Patients were assigned to single-arm cohorts based on HER2 expression. Those in the HER2-positive and the HER2-low cohorts could be assigned to receive zanidatamab plus vinorelbine (Navelbine; n = 20), zanidatamab plus capecitabine (Xeloda; n = 19), or zanidatamab plus paclitaxel (n = 5). Patients with HER2-positive disease could also be assigned to receive zanidatamab plus capecitabine and tucatinib (Tukysa; n = 2). Notably, patients who withdrew from receiving chemotherapy could continue to receive zanidatamab monotherapy.

The primary end point was the frequency and severity of AEs; secondary end points included ORR, disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).

In the overall population, the median age was 54 years (range, 35-72), and 98% of patients were female. Races included Asian (54%), White (41%), Black (2%), and unknown (2%). Additionally, patients had an ECOG performance status of 0 (54%) or 1 (46%); a prior history of brain metastases was reported in 26% of patients. HER2 statuses included HER2 positive (67%) and HER2 low (33%). The median number of prior systemic therapies for metastatic disease was 3 (range, 1-13).

Prior HER2-targeted therapy included trastuzumab (HER2-positive cohort, 100%; HER2-low cohort, 80%), T-DM1 (100%; 73%), pertuzumab (87%; 67%), lapatinib (Tykerb; 23%; 27%), tucatinib (6%; 13%), tucatinib/placebo (6%; 0%), T-DXd (6%; 13%), neratinib (Nerlynx; 6%; 7%), margetuximab (Margenza; 3%; 0%), and investigational antibody-drug conjugate (3%; 0%).

Additional Efficacy Data

In the HER2-positive cohort, patients with IHC 3+ disease achieved a cORR of 53% (95% CI, 27%-79%), and those with IHC 2+/FISH-positive disease had a cORR of 31% (95% CI, 9%-61%). Of note, the DCRs were 89% (95% CI, 72%-98%) in the HER2-positive cohort and 67% (95% CI, 38%-88%) in the HER2-low cohort. The median DORs in these respective cohorts were 14.8 months (95% CI, 3.6-not estimable) and 10.4 months (95% CI, 3.7-26.0).

Furthermore, at a median follow-up of 6.2 months (range, 1.9-62.6), the median PFS for patients with HER2-positive and HER2-low metastatic breast cancer was 10.4 months (95% CI, 5.3-16.4) and 3.7 months (95% CI, 1.8-5.4), respectively. At a data cutoff of September 30, 2024, all patients had discontinued the study.

Disclosures: Dr Hamilton reported receiving grants (institution only for consulting advisory roles) from Accutar Biotechnology, Arvinas, AstraZeneca, BeOne Medicines, Circle Pharma, Daiichi-Sankyo, Entos, Gilead Sciences, Halda Therapeutics, Incyclix Bio, IQVIA, Janssen, Jazz Pharmaceuticals, Jefferies LLC, Johnson and Johnson, Lilly, Medical Pharma Services, Mersana, Novartis, Pfizer, Tempus Labs, and Zentalis Pharmaceuticals; having research contracts with or receiving funding (institution only) from AbbVie, Accutar Biotechnology, Acerta Pharma, Stemline Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeOne Medicine, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Cascadian Therapeutics, Clovis, Compugen, Context Therapeutics, Cullinan, Curis, CytomX, Daiichi-Sankyo, Dana-Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Eisai, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon Pharmaceuticals, FujiFilm, G1 Therapeutics, Gilead Sciences, H3 Biomedicine, Harpoon, Huchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, Inspirna, InventisBio, Jacobio, Karyopharm, K-Group Beta, Kind Pharmaceuticals, Leap Therapeutics, Lilly, Loxo Oncology, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Mersana, Merus, Millenium, Molecular Templates, Myriad Genetic Therapeutics, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Immune Medicine, Rgenix, Roche/Genentech, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, StemCentRx, Stemline Therapeutics, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Zenith Epigenetics, and Zymeworks.

References

1. Bedard PL, Im S, Elimova E, et al. Zanidatamab + chemotherapy for patients with HER2-expressing metastatic breast cancer: final results of a phase 1 trial. Presented at: 2025 ESMO Breast Congress; May 14-17, 2025; Munich, Germany. Abstract 303MO.
2. Weisser NE, Sanches M, Escobar-Cabrera E, et al. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity. Nat Commun. 2023;14(1):1394. doi:10.1038/s41467-023-37029-3