Up to 50% of patients with metastatic triple-negative breast cancer and HER2-positive breast cancer will have brain metastases, representing a treatment challenge in clinical practice. In this setting, HER3 overexpression is implicated in the resistance to HER2-targeted therapies and is a driver of brain metastasis, whereas the 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 will evaluate HER2/HER3-directed αDC1 vaccines combined with pembrolizumab in patients with brain metastasis from triple-negative breast cancer or HER2-positive breast cancer. The study’s inclusion criteria were having TNBC and HER2-positive breast cancer with brain metastasis, age ≥18 years, an Eastern Cooperative Oncology Group performance status score of ≥1, normal marrow and organ function, no evidence of leptomeningeal disease, and measurable brain disease per the response assessment in neuro-oncology brain metastases (RANO-BM) criteria (≥1 asymptomatic, untreated, measurable brain metastases of ≥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 adverse events, or withdrawal from the study, for up to 24 months.
The primary end point is the central nervous system (CNS) response rate per the 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 have joined the study; 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 for further evaluation if ≥3 responses are observed. The secondary end points include non-CNS response rate 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 the pre- and posttreatment biopsies of the non-CNS tumor tissue. The exploratory end points include changes in infiltrating T cells, their CD4/CD8 ratios, the frequencies of FOXP3 cells, as well as the expression of chemokine receptors on CD4+ and CD8+ T cells, PD-1, and PD-L1. In addition, the local expression of Teff- and Treg-attracting chemokines will be analyzed. Currently, 2 of the planned 21 patients have been enrolled and are receiving treatment.
Source: 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.