A phase II clinical trial has revealed that the addition of HER-Vaxx, a B-cell peptide-based vaccine, to standard chemotherapy significantly improves overall survival (OS) in patients with HER2-overexpressing metastatic or advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. The study, conducted across multiple centers in Eastern Europe and India, showed a 40% survival benefit with the combination therapy compared to chemotherapy alone, offering a promising new approach for patients with limited first-line treatment options.
Study Design and Patient Population
The randomized, open-label trial enrolled 36 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received chemotherapy or radiotherapy. Patients were randomized to receive either HER-Vaxx (50 μg) plus platinum-based chemotherapy or chemotherapy alone. The primary endpoint was overall survival, with secondary endpoints including progression-free survival (PFS), duration of objective response (DOR), overall response rate (ORR), and safety. Exploratory endpoints included the evaluation of vaccine-induced HER2-specific antibody levels and tumor response rates.
Key Findings
The study demonstrated a statistically significant improvement in overall survival for patients treated with HER-Vaxx plus chemotherapy, with a hazard ratio (HR) of 0.6 as determined by Blinded Independent Central Review (BICR). The median DOR was 7.1 months in the HER-Vaxx arm compared to 4.4 months in the chemotherapy-alone arm. While the ORR was similar between the two groups (37% vs. 41%), the HER-Vaxx-induced IgG antibodies strongly correlated with tumor regression (p = 0.001).
Immunological Response and Mechanism of Action
HER-Vaxx induced a strong humoral immune response, characterized by high levels of HER2-specific IgG and IgG1 antibodies. These antibodies were shown to mediate antibody-dependent cellular cytotoxicity (ADCC) and inhibit intracellular phosphorylation of HER2 and downstream signaling molecules like Akt and MAPK. Furthermore, vaccination with HER-Vaxx was associated with a significant reduction in the number of regulatory T cells (Treg), suggesting a counteraction of immune tolerance effects.
Safety and Tolerability
The addition of HER-Vaxx to chemotherapy did not result in any significant increase in treatment-emergent adverse events (TEAE). The rates of any TEAE were comparable between the two arms (95% vs. 94%), and the most common adverse events in the HER-Vaxx arm included headache, decreased appetite, diarrhea, and nausea. These findings indicate that HER-Vaxx is safe and well-tolerated in combination with standard chemotherapy.
Clinical Implications
These results suggest that HER-Vaxx, as an active immunotherapy, can enhance the efficacy of chemotherapy in patients with HER2-overexpressing gastric cancer. The induction of a strong and durable antibody response, coupled with the modulation of immune tolerance, highlights the potential of HER-Vaxx as a valuable addition to the treatment landscape for this aggressive malignancy. Further studies, including ongoing phase II trials evaluating HER-Vaxx in combination with other targeted therapies, are warranted to fully elucidate the clinical benefit of this novel vaccine.
