A phase I/II trial of avelumab combinations with ivuxolimab, utomilumab, and radiation therapy in patients with advanced gastrointestinal malignancies

Background: Checkpoint agonists utomilumab (4-1BB agonist) and ivuxolimab (OX40 agonist) enhance Teffector cell function. Preclinical studies suggest that combining these drugs with avelumab (anti-PD-L1 antibody) can potentially synergize this effect. In addition, tissue abscopal effects of radiation therapy may improve antigen presentation, complementing PD-L1 blockade. We conducted a single institution, open-label, multi-arm, non-randomized, phase 1/2 clinical trial of avelumab in combination with ivuxolimab, with or without utomilumab, and radiation therapy in patients with advanced solid tumors. Herein, we present a subgroup analysis in patients with gastrointestinal (GI) tumors (pancreatic, colon, gastric, and hepatocellular). Methods: The primary objectives of this study were to assess safety, tolerability, and dose-limiting toxicities. The secondary objectives were to evaluate efficacy including response rate, progression free survival (PFS), as determined by immune-related Response Criteria in Solid Tumors (irRECIST) and overall survival (OS). Results: Thirty-one patients with pancreatic (n = 21), colorectal (n = 8), hepatocellular (n = 1), and gastric (n = 1) cancers were included in this study. The most common treatment-related adverse events (TRAEs) were chills (13%), diarrhea (10%), colitis (10%), fatigue (6%), and fever (6%). There were 3 instances of grade 3 diarrhea and colitis (10%) without any other grade ≥ 3 TRAEs Among the 24 patients evaluable for response, 9 (37.5%) had immune-related stable disease (irSD) and 14 (58.3%) had immune-related progressive disease (irPD). One patient had clinical progression without radiological confirmation. The median PFS was 2 months. Median OS was 5.6 months. Conclusion: Combining avelumab with co-stimulatory checkpoint agonists produces modest activity without added safety concerns in patients with advanced GI malignancies (ClinicalTrials.gov Identifier: NCT03217747).