A phase II study of agenT-797 (invariant natural killer T-cells), botensilimab (Fc-enhanced CTLA-4 inhibitor) and balstilimab (anti-PD-1) in patients with advanced, refractory gastroesophageal adenocarcinoma.

TPS515 Background: Esophagogastric (EG) cancer, the fifth most common cancer worldwide and second leading cause of cancer-related mortality, results in 1.3 million deaths annually. Despite recent advances in frontline management, nearly all patients with metastatic disease experience progression, highlighting the urgent need for novel therapies. Botensilimab (BOT), an Fc-enhanced, multifunctional anti-CTLA-4 antibody, has shown promise in combination with balstilimab (BAL, anti-PD-1) across multiple treatment-refractory cancers. Additionally, agenT-797, an allogeneic off-the-shelf invariant Natural Killer T (iNKT) cell therapy, enhances immune responses, including in settings refractory to immune checkpoint inhibitors (ICI), without requiring HLA matching or lymphodepletion. In a cohort of 82 previously treated patients, agenT-797 demonstrated a favorable safety profile with no severe Cytokine Release Syndrome, Graft-versus-Host Disease, or immune effector cell-associated neurotoxicity syndrome. Notably, in patients with relapsed/refractory gastric cancer, agenT-797 plus anti-PD-1 showed important clinical activity that warrants further exploration. Given their complementary mechanisms of action in modulating anti-tumor immunity, we aimed to evaluate the safety and efficacy of combining BOT, BAL, and agenT-797 with standard ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) and paclitaxel chemotherapy in patients with advanced EG cancer who have progressed on frontline therapy. Methods: This is an investigator-initiated, single-arm phase II trial in adult patients (≥18 years) with esophageal, gastric, or gastro-esophageal junction (GEJ) adenocarcinoma who have received one prior line of therapy, performed at Memorial Sloan Kettering Cancer Center. Eligible patients receive a single infusion of agenT-797 on cycle 1 day 1, BOT 75 mg on day 1 of cycles 1 through 3, BAL 240 mg on days 1 and 15, ramucirumab 8 mg/kg on days 1 and 15, and paclitaxel chemotherapy 80 mg/m 2 on days 1, 8, and 15 of a 28-day cycle. Treatment is continued until disease progression (defined by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint is overall response rate. The secondary endpoints are safety and tolerability, disease control rate, duration of response, progression-free survival, and overall survival. The regimen will be considered worthy of further investigation if at least 15 out of 37 patients achieve an objective response. To date, 12 patients have been enrolled and started on treatment. This trial is registered with ClinicalTrials.gov, NCT06251793. Clinical trial information: NCT06251793 .