Background: HER-Vaxx is a B-cell peptide vaccine composed of a fusion of 3 epitopes from the extracellular domain of HER2/neu conjugated to CRM197 with the adjuvant Montanide. Results from a phase 1b study revealed that active immunization with HER-Vaxx was well tolerated and induced HER2-dose dependent immune responses corresponding to tumor reduction in advanced gastric cancer (GC) or gastroesophageal adenocarcinoma (GEA) (Wiedermann, 2021). A phase 2 study, HERIZON, comparing HER-Vaxx plus standard chemotherapy or chemotherapy alone is currently enrolling. Pre-clinical data demonstrated a synergistic effect with combination of HER2 and PD-1 vaccines and 90% tumor growth inhibition (Kaumaya, 2020). Ramucirumab plus paclitaxel is an approved second-line treatment for patients with GC or GEA who have failed first-line treatment chemotherapy or trastuzumab (TRA) (Wilke, 2014). The nextHERIZON study seeks to evaluate the clinical benefit of adding HER-Vaxx to ramucirumab plus paclitaxel or pembrolizumab, following progression on TRA. Methods: nextHERIZON is phase 2, open-label, non-comparative, double arm, 2-stage design study in patients with confirmed AGC and HER2 overexpression following progression on or after TRA. Arm assignment depends on prior PD-1/PD-L1 inhibitor treatment. Arm 1 will receive HER-Vaxx + ramucirumab and paclitaxel. Arm 2 will receive HER-Vaxx + pembrolizumab. Up to 55 patients will be enrolled in each arm which includes a safety run-in phase. Arms will be analyzed independently. The key inclusion criteria are: patients ³ 18 year of age; ECOG 0 or 1; minimum life expectancy of 3 months; progressed on or after TRA; confirmed HER2 overexpression; at least one measurable lesion; adequate hematologic and organ function. Key exclusion criteria include previous treatment with trastuzumab-deruxtecan or any other anti-HER2 therapy other than trastuzumab. Arm 2 excludes prior therapy with anti- PD-1, PD-L1 or PD-L2 agents. The co-primary endpoints are safety and objective response rate (RECIST 1.1). Secondary objectives are efficacy and survival measures. HER-Vaxx is administered by intramuscular (IM) injection on Day 1, Day 15, and Day 29 and on Day 1 of each 2^nd or 3^rd cycle depending on arm. Dose-limiting toxicity (DLT) window is 29 days on treatment. Tumor assessment is evaluated at Day 43 then every 6 weeks until progression or withdrawal. This study is currently enrolling patients in Australia and US (Q1 2023). Clinical trial information: NCT05311176.