Background: Active immunization with the B-lymphocyte stimulating HER2 vaccine, HER-Vaxx (IMU-131), has shown clinical response correlated with HER2-specific antibodies (Wiedermann et. al., Clinical Cancer Research, 2021). The HER-Vaxx HERIZON study is based on the landmark ToGA study (Bang et. al., The Lancet, 2010) and included patients with HER2/neu over-expressing metastatic or advanced gastric/GEJ adenocarcinoma who were naïve to HER2 therapy. Methods: Thirty-six patients were randomized to either HER-Vaxx plus standard chemotherapy or standard chemotherapy alone. The primary endpoint was overall survival (OS). HER-Vaxx plus chemotherapy treated patients received 50 µg dose of HER-Vaxx by intra-muscular injection at Days 0, 14, 35, 77 and every 63 days until disease progression. Both groups received chemotherapy starting at Day 0 and then every 21 days for a maximum of 6 cycles or until disease progression. Standard chemotherapy consisted of cisplatin + 5FU or capecitabine, or oxaliplatin + capecitabine. Statistical analysis pre-specified a 1-sided false positive probability of 0.10. Results: Of 36 patients randomized (19 treated with HER-Vaxx plus chemotherapy and 17 with chemotherapy alone), 32 patients had a survival event (15 and 17 respectively) at the time of final analysis. All patients received oxaliplatin + capecitabine chemotherapy. Analysis showed a 42% survival benefit for patients treated with HER-Vaxx plus chemotherapy compared to chemotherapy alone. This translated into an OS HR of 0.580 (80% 2-sided CI: 0.362, 0.927) with a statistically significant p-value of 0.066. The median OS for patients receiving HER-Vaxx plus chemotherapy was 13.9 (7.5, 14.3) months, compared to 8.3 (6.0, 9.6) months in patients treated with chemotherapy alone. Median duration of response was 30 vs 19 weeks in favor of the HER-Vaxx arm. There was no difference in safety between the two treatment arms, indicating HER-Vaxx does not add toxicity to standard chemotherapy. HER-Vaxx induced persistent HER2 specific antibodies which correlated with clinical response. Additional response parameters including DOR and biomarker data will be presented at the meeting. Conclusions: These data demonstrate that in patients with HER2 over-expressing gastric/GEJ cancer active HER2 immunization with HER-Vaxx is safe and provides relevant clinical benefit over standard of care chemotherapy. Clinical trial information: NCT02795988.