HERIZON: A phase 2 study of HER-Vaxx (IMU-131), a HER2t-argeting peptide vaccine plus SOC chemotherapy in patients with HER2+advanced stomach cancer - correlation of the antibody responses and clinical outcome

One of the most important targets in human malignancies is Her-2/neu, a member of the epidermal growth factor receptor (EGFR) family, overexpressed not only in breast cancer but also in 6%-30% of gastric cancers. HER-Vaxx is a B cell peptide-based anti-Her-2/neu vaccine (IMU-131) comprising trastuzumab’s binding site. In the phase 1b HERIZON trial (NCT02795988), HER-Vaxx has been shown to be safe and to prolong progression-free survival in patients with Her2/neu-overexpressing gastric/gastro-esophageal junction cancer (GC). The present randomized phase 2 open-label, multicenter study, compared HER-Vaxx plus chemotherapy vs chemotherapy alone and aimed to evaluate antibody and clinical responses in patients with advanced or metastatic Her2 overexpressing GC naïve to Her-2/neu therapy. Patients were randomized to chemotherapy alone (n=17) or HER-Vaxx plus chemotherapy (n=19). In the vaccination group, patients received a 50μg dose of the vaccine at days 0, 14, 35, and 77 followed by q. 63 days until disease progression. Chemotherapy consisted of oxaliplatin plus capecitabine and was started at day 0, repeated q. 21 days for a maximum of 6 cycles. Specific anti-Her-2-antibody levels (IgG and its isotypes) in the patient’s sera were evaluated by ELISA and clinical responses assessed by RECIST 1.1 criteria. Regression analyses of log fold change of tumor diameter on log IgG (and isotypes) as well as comparisons between groups of the concentrations of IgG and isotypes were done by Generalized Estimation Equations with linear contrasts applying sequential Sidak correction. Evaluation of the antibody responses showed that HER-Vaxx induced significant levels of Her-2-specific IgG (P<0.001) and IgG1 (P<0.001) at all time points after 3 or more vaccinations, as compared to patients from the chemotherapy-only group in whose sera no specific induction of anti-Her-2/neu antibodies was found. The levels of specific IgG (P=0.001) and IgG1 (P=0.016) antibodies inversely correlated with tumor diameters. No significant correlation was observed between the magnitude of the antibody responses and the anti-tumor effect in the chemotherapy-only group (P=0.0973) and between the IgG2 (P=0.082), IgG3 (P=0.153) and IgG4 (P=0.236) antibody responses and the anti-tumor effect in the vaccinated group. HER-Vaxx-based vaccination of patients with Her-2 overexpressing GC-induced anti-Her-2-IgG and -IgG1 subclass antibody responses and the magnitude of these antibody responses (total IgG and IgG1) correlated with tumor size reduction. The present data, its previously shown favorable safety profile as well as improved overall survival data induced by HER-Vaxx in Her-2/neu overexpressing GC validate the proof of concept for a first-in-class B-cell immunotherapy based on Her-2/neu peptides.