Neoadjuvant Zanidatamab Shows Early Efficacy, Early Tolerability, Node-Negative, HER2+ Breast Cancer

Neoadjuvant zanidatamab (ZW25) monotherapy successfully reduced the incidence of residual disease and was well tolerated in treatment-naïve women with node-negative, stage I HER2-positive breast cancer, enabling patients to potentially achieve pathological complete responses (pCRs) in the absence of chemotherapy, according to data from a phase 2 pilot trial (NCT05035836) presented at the 2023 ESMO Breast Cancer Annual Congress.1

Of patients who received 3 courses of zanidamab, 64% achieved pCR or minimal residual disease (RCB-1) according to the Residual Cancer Burden (RCB) index. Four patients (36%) achieved a pCR, 3 (28%) were RCB-1 and 4 (36%) had moderate residual disease (RCB-2).

“Neoadjuvant zanidamab for 3 cycles demonstrated significant efficacy in patients with stage I node-negative HER2+ breast cancer…and was well tolerated with [an] acceptable safety profile,” lead study author Vicente Valero, of the University of Texas MD Anderson Cancer Center, and colleagues wrote in a poster about the data.

Previous data from a phase 1 study (NCT02892123) showed that zanidamab was tolerable in patients with HER2-expressing or HER2-enhanced cancers. No dose-limiting toxicities were observed with the bispecific antibody in the dose-escalation phase of the study and the maximum tolerated dose was not reached.2 In parts 1 and 2, the most common treatment-emergent adverse reactions (TRAEs) of any grade were diarrhea (52% vs. 43%, respectively) and infusion reactions (42% vs. 34%). Only six grade 3 TRAEs were reported in 3% of the patient population (n = 132). Patients evaluable for efficacy achieved an objective response rate of 37% (95% CI, 27.0%-48.7%) in the dose expansion phase of the study (n = 83) and most patients received zanidatamab 20 mg/kg every 2 weeks.

Based on these findings, the researchers hypothesized that using this novel bispecific antibody could provide a safe and effective chemotherapy-free regimen for this population.

The single-arm, open-label phase 2 trial enrolled patients over 18 years of age who had clinically and radiographically node-negative HER2-positive breast cancer with no known metastasis. HER2 positivity was defined as 3+ by immunohistochemistry (IHC) or 2+ IHC with positive in situ hybridization. Patients were required to be in a non-reproductive status or use appropriate contraception during the study. Other inclusion criteria included a pre-treatment tumor size between 1 cm and 3 cm as determined by ultrasound, normal left ventricular ejection fraction (LVEF) 4 weeks prior to treatment, and adequate organ and bone marrow function.

All patients in the study received prophylactic treatment for infusion-related toxicities prior to zanidamab administration. The bispecific antibody was then administered intravenously at a dose of 20 mg/kg every 2 weeks for a total of 6 doses in 3 cycles. Peripheral blood analysis was performed at the time of each dose administration. A biopsy was performed before treatment and 6 weeks after the first study dose.

Specifically, premenopausal or postmenopausal patients with estrogen receptor positive disease also received a daily dose of endocrine therapy from Day 1 of Cycle 1; this consisted of 20 mg tamoxifen once daily or 2.5 mg letrozole once daily, respectively. Premenopausal patients could receive letrozole with a gonadotropin-releasing hormone (GnRH) agonist / antagonist according to physician preference. Patients then proceeded to surgical resection followed by adjuvant therapy at the physician’s discretion.

The primary objective of the study was to assess the efficacy of zanidatamab by pCR. The study used Simon’s design criterion to determine the necessary percentage of patients needed to achieve a pCR to declare significance. Researchers aimed for a pCR rate of 25% against a zero rate of 5%.

Secondary objectives included evaluating pathological response by RCB, radiological response, identifying potential predictive biomarkers of response, and investigating the feasibility, safety, and tolerability of zanidatamab. The main exploratory objectives included investigating the levels and dynamics of circulating tumor DNA (ctDNA) and the effect of zanidatamab on the immune system microenvironment.

The median age for this patient population was 61 years (range 30-72). Of the 11 patients enrolled, 7 were postmenopausal and 4 were premenopausal. With regard to HER2 status, 9 patients were HER2 positive by 3+ IHC, and 2 were HER2 positive by 2+ IHC and positive FISH. The median tumor size was 2.2 (range: 1-3). Five patients had tumors between 1 cm and 1.9 cm, and 6 patients had a tumor between 2 cm and 3 cm in size.

In terms of tumor subtype, 5 patients had ER and progesterone receptor (PR) positive disease, 5 patients had ER and PR negative disease, and 1 patient had ER positive and PR negative subtype. Of those with ER-positive disease, 3 patients received tamoxifen and 3 patients received letrozole.

Safety analysis showed that zanidatamab had an acceptable toxicity profile and did not result in any Grade 3 or 4 TRAEs. Common Grade 1/2 adverse reactions were alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 2), fatigue (n = 4), diarrhea (n = 9), alkaline phosphatase elevation (n = 3) , hyperglycemia (n = 4), GERD (n = 2), anemia (n = 2), hypertension (n = 1), rigor (n = 1), pruritus (during infusion, n = 1; intermittent, n = 1 ), oral mucositis (n = 1), menstrual irregularities/spotting (n = 1), rash (n = 4), headache (n = 2), tinnitus (n = 2), anorexia (n = 1), hot flushes ( n = 1), dysgeusia (n = 1), rhinorrhea (n = 1), and muscle cramps (n = 1).

This trial is currently underway and aims to enroll a total of 20 patients. In addition, the trial protocol has been modified to extend the duration of treatment from 6 to 10 cycles for a total of 5 months.

Disclosure: All authors declared no conflicts of interest.


  1. Valero V, Mouabbi J, Alonzo H, et al. Neoadjuvant zanidamab for stage I node-negative HER2-positive breast cancer (BC). Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Summary 132P.
  2. Meric-Bernstam F, Beeram M, Hamilton E, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol. 2022;23(12):1558-1570. doi:10.1016/S1470-2045(22)00621-0

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