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


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Neoadjuvant zanidatamab 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, potentially allowing patients to achieve pathologic complete responses in the absence of chemotherapy.

Vicente Valero

Vicente Valero

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, potentially allowing patients to achieve pathologic 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 the patients who received 3 cycles of zanidatamab, 64% achieved a 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 zanidatamab for 3 cycles showed 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 on the data.

Previous data from a phase 1 trial (NCT02892123) showed that zanidatamab was tolerable in patients with HER2-expressing or HER2-amplified cancers. No dose-limiting toxicities were observed with the bispecific antibody in the dose-escalation phase of the trial, and the maximum tolerated dose was not reached.2 In parts 1 and 2, the most common any-grade treatment-related adverse effects (TRAEs) 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). Efficacy-evaluable patients across all tumor subtypes in the dose-expansion phase of the trial (n = 83) achieved an objective response rate of 37% (95% CI, 27.0%-48.7%) with most patients receiving zanidatamab at 20 mg/kg every 2 weeks.

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

The single-arm, open-label, phase 2 trial enrolled patients older than 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 have non-reproductive status or utilize appropriate contraception during the study. Other inclusion criteria included a pre-treatment tumor size between 1 cm and 3 cm as assessed by ultrasound, normal left ventricular ejection fraction (LVEF) 4 weeks before treatment initiation, and adequate organ and marrow function.

All patients in the study were given prophylactic treatment for infusion-related toxicities prior to zanidatamab 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 conducted at the time of each dose administration. A biopsy was performed before treatment and 6 weeks after the first study dose.

Notably, premenopausal or postmenopausal patients with estrogen receptor–positive disease were also given a daily dose of endocrine therapy starting day 1 of cycle 1; this consisted of either 20 mg of tamoxifen once daily or 2.5 mg of letrozole once daily, respectively. Premenopausal patients were able to receive letrozole with a gonadotropin-releasing hormone (GnRH) agonist/antagonist according to physician’s preference. Patients then continued to surgical resection followed by physician’s choice of adjuvant therapy.

The study’s primary objective was to assess the efficacy of zanidatamab according to pCR. The study utilized Simon’s design criterion to determine the necessary percentage of patients required to achieve a pCR to declare significance. Researchers targeted a pCR rate of 25% against a 5% null rate.

Secondary objectives included evaluating pathologic response according to RCB, radiologic response, identifying potential predictive biomarkers for response, and examining the feasibility, safety, and tolerability of zanidatamab. Key exploratory objectives included examining circulating tumor DNA (ctDNA) levels and dynamics and the effect of zanidatamab on the immune 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. Regarding HER2 status, 9 patients were HER2-positive according to 3+ IHC, and 2 were HER2-positive according to 2+ IHC and positive FISH. 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 that was 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 the ER-positive and PR-negative subtype. Among 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 AEs included alanine aminotransferase increase (n = 3), aspartate aminotransferase increase (n = 2), fatigue (n = 4), diarrhea (n = 9), alkaline phosphatase levels increase (n = 3), hyperglycemia (n = 4), GERD (n = 2), anemia (n = 2), hypertension (n = 1), rigors (n = 1), pruritis (during infusion, n = 1; intermittent, n = 1), oral mucositis (n = 1), irregular menstruation/spotting (n = 1), rash (n = 4), headache (n = 2), tinnitus (n = 2), anorexia (n = 1), hot flashes (n = 1), dysgeusia (n = 1), rhinorrhea (n = 1), and muscle cramps (n = 1).

This trial is currently ongoing and aims to enroll a total of 20 patients. Additionally, trial protocol has been modified to increase 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 zanidatamab for stage I node negative HER2 positive breast cancer (BC). Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 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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