Phase II Trial of HER-Vaxx, a B-cell Peptide-Based Vaccine, in HER2-Overexpressing Advanced Gastric Cancer Patients Under Platinum-Based Chemotherapy (HERIZON)

Abstract

Purpose: A multicenter, randomized, open-label, phase II study (HERIZON; NCT02795988) was conducted to evaluate the clinical and immunologic efficacy of HER-Vaxx (IMU-131), a B-cell, peptide-based vaccine targeting HER2 overexpressed in 6% to 30% of gastroesophageal adenocarcinomas (GEA).

Patients and methods: Patients (n = 36) with GEA were treated with standard-of-care chemotherapy (n = 17) or HER-Vaxx plus chemotherapy (n = 19), using the recommended phase 2 dose for the vaccine. Overall survival (OS; primary endpoint), safety, progression-free survival (PFS), clinical response (secondary endpoints), and vaccine-induced HER2-specific antibody levels in serum and correlation with tumor response rates (exploratory endpoints) were investigated.

Results: A 40% OS benefit [HR, 0.60; median OS, 13.9 months; 80% confidence interval (CI), 7.52-14.32] for patients treated with HER-Vaxx plus chemotherapy compared with OS of 8.31 months (80% CI, 6.01-9.59) in patients that received chemotherapy alone. A 20% PFS difference was obtained for the vaccination arm (HR, 0.80; 80% CI, 0.47, 1.38). No additional toxicity due to HER-Vaxx was observed. The vaccine-induced high levels of HER2-specific total IgG and IgG1 antibodies (P < 0.001 vs. controls) that significantly correlated with tumor reduction (IgG, P = 0.001; IgG1, P = 0.016), had a significant capacity in inhibiting phosphorylation of the intracellular HER2-signaling pathways, mediated antibody-dependent cellular cytotoxicity, and decreased immunosuppressive FOXP3+ regulatory T cells.

Conclusions: HER-Vaxx plus standard chemotherapy exhibits an excellent safety profile and improves OS. Furthermore, vaccine-induced immune response was significantly associated with reduced tumor size compared with standard-of-care chemotherapy. The presented vaccination approach may substitute for treatment with trastuzumab, upon unavailability or toxicity, based on further evidence of equivalent treatment efficacy.

Figure 1.

Study arms and treatment schedule. The timepoints for the patients’ initial screening and the assessment of their tumors are indicated by the arrow boxes. CC, chemotherapy cycle; D, day; Vac, HER-Vaxx administration; W, week.

Figure 2.

TEAE associated with the respective treatments in the study arms. The values at the bottom of each bar indicate the number of patients who experienced the respective TEAE.

Figure 3.

Kaplan–Meier estimate of OS based on ITT analysis. Censored patients are indicated by the “+”. Two patients in the HER-Vaxx plus chemotherapy arm were alive at the end of the study.

Figure 4.

Detected levels of HER2-specific total IgG antibodies. The HER2-specific total IgG antibodies in patients treated with chemotherapy alone A, and 50 µg of HER-Vaxx plus chemotherapy B, measured by ELISA, are shown. The results are representative of at least two experiments.

Figure 5.

Correlation between the induced HER2-specific antibody levels and antitumor effect and mediation of ADCC. The total IgG A, and IgG1 B, antibody levels in all subjects’ available sera after four vaccinations (week 12; Fig. 1) and the observed antitumor effect (as fold change compared with baseline) in each respective patient are shown. The correlation of the induced HER2-specific IgG C, or IgG1 D, antibody levels in representative sera of low, high, and very high responders [after four vaccinations (week 12) with 50- or 100-µg vaccine dose], and ADCC expressed in percent of the positive control (trastuzumab) are presented. The levels of correlation and significance are indicated in the boxes. The target cells NCI-N87 were incubated with effector cells (i.e., PBMC) after treatment with 50 μg of the examined patients' isolated and purified total IgG antibodies. Trastuzumab as a positive control and serum samples from a healthy individual as a negative control were included in the assays. The results represent at least two experiments.