Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients

Abstract

Background: E75 (nelipepimut-S) is a human leukocyte antigen (HLA)-A2/A3-restricted immunogenic peptide derived from the HER2 protein. We have conducted phase I/II clinical trials vaccinating breast cancer patients with nelipepimut-S and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting to prevent disease recurrence. All patients have completed 60 months follow-up, and here, we report the final analyses.

Patients and methods: The studies were conducted as dose escalation/schedule optimization trials enrolling node-positive and high-risk node-negative patients with tumors expressing any degree of HER2 (immunohistochemistry 1-3+). HLA-A2/3+ patients were vaccinated; others were followed prospectively as controls. Local and systemic toxicity was monitored. Clinical recurrences were documented, and disease-free survival (DFS) was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests.

Results: Of 195 enrolled patients, 187 were assessable: 108 (57.8%) in the vaccinated group (VG) and 79 (42.2%) in the control group (CG). The groups were well matched for clinicopathologic characteristics. Toxicities were minimal. Five-year DFS was 89.7% in the VG versus 80.2% in the CG (P = 0.08). Due to trial design, 65% of patients received less than the optimal vaccine dose. Five-year DFS was 94.6% in optimally dosed patients (P = 0.05 versus the CG) and 87.1% in suboptimally dosed patients. A voluntary booster program was initiated, and among the 21 patients that were optimally boosted, there was only one recurrence (DFS = 95.2%).

Conclusion: The E75 vaccine is safe and appears to have clinical efficacy. A phase III trial evaluating the optimal dose and including booster inoculations has been initiated.

Clinical trials: NCT00841399, NCT00584789.

Keywords: breast cancer; immunotherapy; nelipepimut-S; vaccine.

Figure 1.

Flow of patients through the study. *Optimally boosted was defined as beginning booster inoculations six months after completion of the primary vaccinations series.

Figure 2.

Vaccine toxicity. Maximum local and systemic toxicity during the (A) primary vaccination series or (B) booster inoculations. Common local toxicities were injection site erythema or pruritis. Common systemic toxicities were bone pain, influenza-like symptoms, and fatigue (associated with the granulocyte–macrophage colony-stimulating factor).

Figure 3.

In vivo immune responses. (A) Delayed-type hypersensitivity (DTH) for all patients after vaccination. (B) Pre- and postvaccination DTH for node-negative patients. (C) Postvaccination DTH responses by dosing group.

Figure 4.

Disease-free survival. (A) All assessable patients; (B) patients with HER2 1+ or 2+ disease. (C) By dosing group (*P value compares optimally dosed group to control group); (D) evaluating optimally boosted patients (*P value compares optimally boosted group to control group).