Outcome of patients (pts) w/ stage I node neg HER2+ treated w/ wkly paclitaxel x 12 doses and trastuzumab x 1yr is excellent (10yr RFS 96%). Therefore, trials to de-escalate chemo and use targeted therapy alone are underway. Zanidatamab is a novel, humanized, bispecific, immunoglobulin G isotype 1-like, monoclonal antibody directed against the juxtamembrane extracellular domain (ECD4) and the dimerization domain (ECD2) of HER2. This results in HER2 clustering that modulates signaling and leads to immune activation. Zanidatamab demonstrated antitumor activity in heavily pre-treated HER2+ metastatic BC with acceptable safety profile. We
Pts w/ 1-3cm, clinically node neg HER2+ BC were enrolled in this investigator-initiated clinical trial. Pts had HER2+ BC: HER2 3+ by IHC or IHC 2+ and ISH +. Pts received 2-wkly zani x6 prior to surgery. Pts with ER+ tumors also received neoadjuvant endocrine therapy: postmenopausal pts received letrozole 2.5mg daily, and premenopausal pts received tamoxifen 20mg daily or GNRH and letrozole 2.5mg on treating physician preference. The primary objective was to evaluate efficacy as determined by pathologic complete response (pCR). Secondary objectives included pathologic response by residual cancer burden (RCB), radiological response, and safety profile of zanidatamab.
Eleven pts w/ HER2+ BC were enrolled. Median age was 61yrs old (range 30-72). Median tumor size was 2.2cm (range 1-3cm). Four pts were pre-menopausal. Six pts had tumors >2cm tumors. Three received tamoxifen and 3 letrozole. All pts completed 6 cycles of zanidatamab and had Sx. Four (36%) had pCR, 3 RCB1 (28%) and 4 RCB2 (36%). This met the success criterion of Simon’s design (>=3/17 pts with pCR) of targeting a 25% pCR rate against a 5% null rate. Treatment was tolerated well. There were no grade 3 or 4 toxicities. One pt had minor infusion-related reaction and grade 2 acne, and 1 grade 2 diarrhea.
Neoadjuvant zanidatamab for 3 months showed significant efficacy, (pCR/RCB-1 64%) w/ acceptable safety profile in pts w/ stage I node neg HER2+ BC. The trial is ongoing and has been modified to increase treatment duration to 5mths (10 cycles).
The authors.
Zymeworks Inc.
All authors have declared no conflicts of interest.