64 A Phase I/II Study of Pembrolizumab and Anti-CD3 x Anti-HER2 Armed Activated T-Cells in Metastatic Breast Cancer

Background

Treatment of metastatic breast cancer remains a clinical challenge, with a need for novel therapeutic strategies such as T-cell therapies. Arming activated T-cells with anti-CD3 x anti-HER2 bispecific antibodies makes every T-cell into a HER2-specific cytotoxic T-lymphocyte (HER2 BATs). In our previous phase 1 clinical trial, evaluation of immune responses in subjects who received HER2 BATs suggested that they induce robust anti-tumor immune responses, regardless of the subject’s HER2 status, and that infusion of HER2 BATs is safe and feasible. There is strong interest in combining active immunotherapy strategies, such as T-cell therapy, with immune checkpoint inhibitors. We developed this study to assess the feasibility, safety, and preliminary efficacy of HER2 BATs in combination with pembrolizumab in subjects with metastatic breast cancer.

Methods

This was a phase 1/2 clinical trial conducted at the University of Virginia with the primary objective being to determine the maximum tolerated dose (MTD) of HER2 BATs in combination with pembrolizumab and to evaluate safety and toxicity of the MTD in a dose expansion cohort (DEC). The secondary objectives were to estimate efficacy and evaluate immune responses. Eligible patients included women with metastatic breast cancer regardless of hormone receptor or HER2 status, who had received at least 2 prior lines of therapy in the metastatic setting. In a 3+3 dose escalation design, patients received 8 infusions of HER2 BATs and 1 to 3 infusions of pembrolizumab 200 mg. The schedule utilized in the DEC included 3 doses of pembrolizumab.

Results

A total of 17 patients were fully evaluable for efficacy end points. The average number of lines of systemic therapy patients received for metastatic breast cancer prior to enrollment was 4.52. The most common toxicities were chills, headaches, nausea, fatigue, and hypotension. No dose limiting toxicities or high-grade immune-related adverse events were observed. The best response observed was stable disease, seen in 6 (35%) patients, while 11 (65%) had progressive disease by RECIST. The median overall survival was 21.4 months, and median progression-free survival was 3.2 months. Sequential monitoring of serum cytokine patterns and cytotoxicity of peripheral blood mononuclear cells directed at breast cancer cell lines revealed increased serum IL-12 levels and Th1/Th2 ratios after infusion of HER2 BATs, which persisted up to 1-month post-infusion.

Conclusions

This phase 1/2 study showed that the treatment of patients with metastatic breast cancer with HER2 BATs in combination with pembrolizumab is safe and well tolerated. The mean overall survival was comparable to that seen in studies of other heavily pretreated metastatic breast cancer patients, although the best overall response was stable disease.

Previously presented at TRCC 2025.