Anti-HER2/HER3 αDC1 Vaccines Plus Pembrolizumab for Brain Metastasis in Triple-Negative or HER2-Positive BC

Brain metastases develop in up to 50% of patients with metastatic triple-negative breast cancer (TNBC) and HER2-positive breast cancer (BC), representing a treatment challenge in clinical practice. In this setting, HER3 overexpression is implicated in the resistance to HER2-targeted therapies and a driver of brain metastasis, while loss of anti-HER2 and anti-HER3 immunity promotes disease progression, providing the rationale for anti-HER2/3–loaded α dendritic cell 1 (αDC1) vaccines in combination with PD1 blockade.

Based on this hypothesis, an ongoing single-arm, nonrandomized, open-label, multicenter, phase 2 study (NCT04348747) will evaluate HER2/HER3-directed αDC1 vaccine combined with pembrolizumab in patients with brain metastasis from TNBC or HER2-positive BC. Inclusion criteria are patients with TNBC and HER2-positive BC with brain metastasis, age ≥18 years, Eastern Cooperative Oncology Group Performance Status ≥1, normal marrow and organ function, no evidence of leptomeningeal disease, and measurable brain disease per response assessment in neuro-oncology brain metastases (RANO-BM) criteria (≥1 asymptomatic untreated measurable brain metastases ≥0.5 cm and <3 cm).

In the treatment phase, eligible patients will receive anti-HER2/HER3 αDC1 intradermally every 3 weeks combined with pembrolizumab (200 mg, day 1) every 3 weeks for 3 cycles. In the maintenance phase, patients will receive αDC1 booster doses every 3 months (plus pembrolizumab every 3 weeks) until disease progression, intolerable side effects, or withdrawal from the study, up to 24 months.

The primary end point is central nervous system (CNS) response rate (RR) by RANO-BM criteria for the combination of anti-HER2/3 vaccines with pembrolizumab. The study will be terminated if no CNS response is observed after 12 patients; however, if ≥1 CNS response is observed, then 9 more patients will be enrolled for a total of 21 patients. Treatment will be considered promising of further evaluation if ≥3 responses are observed. Secondary end points include non-CNS RR per RECIST version 1.1, overall progression-free survival (PFS), median CNS PFS and non-CNS PFS, overall survival, and safety.

Correlative studies will be performed on pre- and post-treatment biopsies of the non-CNS tumor tissue. Exploratory end points include changes in infiltrating T cells, their CD4/CD8 ratios, frequencies of FoxP3 cells, as well as expression of chemokine receptors on CD4+ and CD8+ T cells, PD-1, and PD-L1. In addition, local expression of Teff-attracting chemokines and Treg-attracting chemokines will be analyzed. Currently, 2 patients of the planned 21 have been enrolled and are undergoing treatment.


Gandhi S, Forsyth PAJ, Opyrchal M, et al. Phase IIa study of aDC1 vaccines targeting HER2/HER3 combined with pembrolizumab in patients with asymptomatic brain metastasis from triple negative breast cancer or HER2+ breast cancer. Abstract presented at: ASCO Annual Meeting, June 2-6, 2023; Chicago, IL. Abstract TPS1112.

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