Phase IIa study of αDC1 vaccines targeting HER2/HER3 combined with pembrolizumab in patients with asymptomatic brain metastasis from breast cancer.

TPS2088 Background: Brain metastases develop in up to 50% of patients (pts) with metastatic breast cancer. Overexpression of HER3 in brain metastatic breast cancer (BMBC) is a resistance factor to HER2-targeted therapies and a driver of brain metastasis. Disease progression is associated with loss of anti-HER2 and anti-HER3 immunity. Previously, we have demonstrated that glioma-specific peptide-loaded αDC1 which produces CXCL9, CXCL10, CXCL11, and CCL5, the chemokines that attract CXCR3- and CCR5- expressing cytotoxic T-lymphocytes (CTLs) and T-helper 1 (Th1) cells, induce clinical responses and long-term disease stabilization in pts with aggressive recurrent primary brain tumors (Okada et al. JCO 2011. PMID: 21149657). We hypothesized that anti-HER2/3-loaded αDC1 combination with PD1 blockade will result in a strong Th1/CTL response against HER2/3 epitopes (Basu A et al. Cancer Immunol Res. 2022 PMID: 34785506) that will translate into anti-cancer benefit in the central nervous system (CNS) and systemically. Methods: This is a phase II single-arm, non-randomized multicenter study (NCT04348747). Eligibility includes pts with BMBC ≥18 years, ECOG PS ≤1, normal marrow and organ function with asymptomatic untreated brain metastases ≥ 5 mm. The study subjects receive αDC1 q3 weeks x 3 along with pembrolizumab every 3 weeks. Thereafter, αDC1 booster doses can be administered every 3 months until disease progression, intolerable side effects, or withdrawal from study, up to 24 months. Baseline and 9-week post-αDC1 peripheral biopsies (non-CNS) are required for six pts. The primary endpoint is CNS response rate (RR) by RANO-BM criteria. If no CNS response is observed after 12 pts, the study will be terminated. If ≥ 1 response is observed, then 9 more pts will be enrolled, for a total of 21 pts. If ≥ 3 CR are observed, the proposed therapy will be considered promising for further evaluation. Secondary endpoints include non-CNS RR per RECIST v1.1, median CNS, non-CNS and overall progression-free survival, overall survival, and safety. Exploratory endpoints include changes in intratumoral biomarkers (CTLs, PDL1, chemokines) in pre- and post-treatment peripheral tumor biopsies and immune changes in the blood. So far, 7 of the planned 21 pts have been enrolled. Clinical trial information: NCT04348747 .