Frontline Zanidatamab Plus Docetaxel Yields Antitumor Activity, Safety in Advanced HER2+ Breast Cancer


The novel HER2-targeted bispecific antibody zanidatamab in combination with docetaxel demonstrated efficacy with a manageable safety profile as first-line treatment in patients with advanced HER2-positive breast cancer.

Zanidatamab Plus Docetaxel in 

HER2+ Breast Cancer | Image Credit: 

© Axel Kock -

Zanidatamab Plus Docetaxel in

HER2+ Breast Cancer | Image Credit:

© Axel Kock -

The novel HER2-targeted bispecific antibody zanidatamab (ZW25) in combination with docetaxel demonstrated efficacy with a manageable safety profile as first-line treatment in patients with advanced HER2-positive breast cancer, according to updated data from a phase 1b/2 study (NCT04276493) presented at the 2023 ASCO Breakthrough Meeting.

At a median follow-up of 15.5 months (range, 1.1-29.3), efficacy-evaluable patients (n = 33) expereinced a confirmed objective response rate (ORR) of 90.9% (95% CI, 75.7%-98.1%). The median duration of response (DOR) was not estimable (NE; 95% CI, 12.1-NE). The confirmed disease control rate (DCR) was 97.0% (95% CI, 84.2%-99.9%); 6- and 12-month progression-free survival (PFS) rates were 93.9% (95 % CI, 77.9%-98.4%) and 73.3% (95% CI, 50.7%-86.7%), respectively.

Zanidatamab binds to 2 non-overlapping extracellular domains of HER2, leading to more potent effector function compared with trastuzumab (Herceptin). Previously, when combined with chemotherapy, zanidatamab demonstrated antitumor activity and a manageable safety profile in patients with advanced HER2-positive breast cancer and HER2-positive gastric/gastroesophageal junction adenocarcinoma.

“Zanidatamab’s unique binding properties result in multiple mechanisms of action, including receptor clustering, internalization, and downregulation; inhibition of growth factor-dependent and -independent tumor cell proliferation; complement-dependent cytotoxicity; and antibody-dependent cellular toxicity and phagocytosis,” lead study author Xiaojia Wang, MD, of the Department of Oncology at the Zhejiang Cancer Hospital in Hangzhou, China, and colleagues wrote in a poster presentation.

The open-label, multicenter, phase 1b/2 trial enrolled patients with unresectable, locally advanced, recurrent or metastatic HER2-positive breast cancer who received no prior systemic chemotherapy or biologic therapy in the advanced setting. An ECOG performance status of 0 or 1 was also required.

Patients enrolled under the study’s original protocol joined cohort A; however, after pharmacokinetic data demonstrated comparable exposure between weight-based and flat dosing, a protocol amendment enrolled patients in cohort B to a fixed dose of zanidatamab. Patients were given zanidatamab at a dose of 30 mg/kg in cohort A (n = 10) or 1800 mg in cohort B (n = 27) in addition to intravenous docetaxel at 75 mg/m2 once every 3 weeks until disease progression or intolerable toxicity. Patients received a median of 13 (range, 1-37) cycles of treatment. Continuation of docetaxel following cycle 6 was at the discretion of the investigator.

The co-primary end points were ORR and adverse effects (AEs)/serious AEs. Secondary end points included DOR, DCR, PFS, and overall survival.

Among all patients evaluable for safety in the phase 1b/2 trial (n = 37), the median age was 55.0 years (range, 33-80). Patients had a HER2 status of immunohistochemistry (IHC) 3+ (86.5%) or IHC 2+/fluorescence in situ hybridization–positive (13.5%). The majority of patients had hormone receptor–positive disease (56.8%), had an ECOG performance score of 1 (73.0%), and did not have brain metastases (94.6%). Additionally, patients were either Chinese (73.0%) or Korean (27.0%). Notably, 43.2% of patients received prior anti-cancer systemic therapies, including (neo)adjuvant anti-HER2 therapy (21.6%), trastuzumab (21.6%), and pertuzumab (Perjeta; 2.7%).

Additional data showed that efficacy-evaluable patients in cohort A (n = 8) achieved a confirmed ORR of 100.0% (95% CI, 63.1%-100.0%). The ORR was 88.0% (68.8% vs 97.5%) for those in cohort B (n = 25). One patient in each cohort achieved a complete response. Two patients (8.0%) in cohort B experienced stable disease, and 1 had progressive disease (4.0%). The median DOR was 12.4 months (95% CI, 5.5-NE) in cohort A and NE (95% CI, 12.1-NE) in cohort B. As of the data cutoff of November 22, 2022, 48.6% of all patients remained on treatment.

Regarding safety in the overall population (n = 37), 97.3% of patients experienced a treatment-related AE (TRAE) of any grade, including 67.6% who had a grade 3 or higher TRAE. Patients in cohort A experienced a rate of grade 3 or higher TRAEs of 90.0%. That rate was 59.3% in cohort B. In cohort A vs cohort B, the most common grade 3 or higher TRAEs included decreased neutrophil count (70.0% vs 40.7%), diarrhea (30.0% vs 0.0%), anemia (10.0% vs 0.0%), and decreased white blood cell count (0.0% vs 25.9%). Serious TRAEs occurred in 10% vs 18.5% of patients, respectively, and 2 of the 6 patients who experienced a serious TRAE had increased blood bilirubin.

There were no dose reductions due to TRAEs in the fixed-dose cohort; however, 20.0% of patients in the weight-based dosing cohort required a dose reduction. TRAEs led to treatment discontinuation in 7.4% of patients in cohort B (7.4%), and none led to death.

Any-grade TRAEs reported in cohort A and cohort B included decreased neutrophil count (70.0% vs 55.6%), anemia (10.0% vs 70.4%), diarrhea (70.0% vs 44.4%), decreased white blood cell count (0.0% vs 59.3%), alopecia (10.0% vs 44.4%), increased alanine transaminase (10.0% vs 37.0%), increased aspartate transaminase (10.0% vs 33.3%), and nausea (40.0% vs 22.2%).


Wang X, Lee KS, Zeng X, et al. Zanidatamab, a HER2-targetd bispecific antibody, in combination with docetaxel as first-line therapy for patients with advanced HER2-positive breast cancer: updated results from a phase 1b/2 study. J Clin Oncol. 2023;41(suppl 16):1044. doi:10.1200/JCO.2023.41.16_suppl.1044

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