A phase I/II trial of avelumab combinations with ivuxolimab, utomilumab, and radiation therapy in patients with advanced gastrointestinal malignancies
Jibran Ahmed, Anne Knisely, Carlos Torrado, Bettzy Stephen, Yali Yang, Juhee Song, Anas Alshawa, Abdulrazzak Zarifa, Anuja Jhingran, Eugene J Koay, Van Karlyle Morris, Milind Javle, Robert A Wolff, Funda Meric-Bernstam, Shubham Pant, Jordi Rodon, Aung NaingAbstract
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).