A combination of zanidatamab and evorpacept has shown promising antitumor activity in patients with HER2-positive metastatic breast cancer, including those who had progressed on prior fam-trastuzumab deruxtecan-nxki (T-DXd), according to phase 1b/2 study data presented at the 2024 San Antonio Breast Cancer Symposium (SABCS). The study also demonstrated activity in heavily pretreated HER2-low metastatic breast cancer.
Efficacy in HER2-Positive Metastatic Breast Cancer
In the cohort of patients with HER2-positive metastatic breast cancer (n = 21), the confirmed overall response rate (ORR) was 33.3% (95% CI, 14.6%-57.0%), with all responses being partial responses (PRs). The disease control rate (DCR) was 71.4% (95% CI, 47.8%-88.7%), and the median progression-free survival (PFS) was 3.6 months (95% CI, 1.8-11.0). Among patients with HER2-positive disease per central assessment (n = 9), the ORR was 55.6% (95% CI, 21.2%-86.3%), while in those without HER2-positive disease via central assessment (n = 12), the ORR was 16.7% (95% CI, 2.1%-48.4%).
Activity in HER2-Low Metastatic Breast Cancer
In the cohort of patients with HER2-low metastatic breast cancer (n = 15), the zanidatamab combination yielded an ORR of 20.0% (95% CI, 4.3%-48.1%), consisting entirely of PRs. The DCR was 40.0% (95% CI, 16.3%-67.7%), the median duration of response (DOR) was 5.5 months (range, 3.6-11.0), and the median PFS was 1.9 months (95% CI, 1.6-3.9).
Study Design and Patient Population
The open-label, multicenter study enrolled patients with previously treated, inoperable, locally advanced, and/or metastatic HER2-expressing breast cancer or other diseases. Patients received zanidatamab at 1200 mg (if under 70 kg) or 1600 mg (if 70 kg or higher) plus evorpacept at 20 mg/kg or 30 mg/kg intravenously every 2 weeks. The primary objective of part 2 of the trial was to assess the antitumor activity of zanidatamab and evorpacept across each cohort.
Safety and Tolerability
Among all evaluable patients in the safety population (n = 52), any-grade treatment-related adverse effects (TRAEs) occurred in 86.5% of patients, with mostly grade 1/2 events. Serious TRAEs were reported in 5.8% of patients, and 3.8% experienced TRAEs resulting in treatment discontinuation. Common TRAEs included diarrhea, fatigue, nausea, and infusion-related reactions (IRRs). No treatment-related deaths were observed.
Expert Commentary
According to Alberto J. Montero, MD, MBA, CPHQ, clinical director of the Breast Cancer Medical Oncology Program at University Hospitals Seidman Cancer Center, "Zanidatamab plus evorpacept showed promising antitumor activity in patients with heavily pretreated HER2-positive [metastatic breast cancer] including after progression on prior fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu]…Antitumor activity was also observed in patients with heavily pretreated HER2-low [metastatic breast cancer]. Based on the results presented here, further development of this novel chemotherapy-free regimen is warranted."
