Phase 1 and 2 Clinical Studies of the STING Agonist Ulevostinag With and Without Pembrolizumab in Participants With Advanced or Metastatic Solid Tumors or Lymphomas

Abstract Purpose: We report results from 2 clinical trials of the cyclic dinucleotide stimulator of interferon genes (STING) agonist ulevostinag. Patients and Methods: In a phase 1 study (Study 1; NCT03010176) with an accelerated titration design/modified toxicity probability interval method, participants with advanced/metastatic solid tumors or lymphomas received intratumoral ulevostinag (±intravenous pembrolizumab). In an expansion phase, participants with head and neck squamous cell carcinoma (HNSCC) or triple-negative breast cancer received the combination. Primary objectives were safety/tolerability and identifying the recommended phase 2 dose (RP2D); biomarkers were exploratory. In a randomized phase 2 study (Study 2; NCT04220866), participants with untreated metastatic or unresectable, recurrent HNSCC received intravenous pembrolizumab (±ulevostinag 540µg). Primary objective was antitumor activity. Pembrolizumab 200mg was administered Q3W in both studies. Results: In Study 1 (N=156), the most common adverse event (AE) was pyrexia (70%). Plasma ulevostinag concentrations increased dose-dependently. Circulating levels of C-X-C motif chemokine 10, interferon-gamma, and interleukin-6 showed elevation at 2–4 hours, peak at 6–8 hours, and plateau/partial resolution at 24 hours but, beyond the 540µg dose, did not show a clear dose-effect relationship. Ten participants experienced dose-limiting toxicities; the RP2D for intratumoral ulevostinag was 540µg. In Study 2, 4/8 participants treated with combination therapy and 1/10 treated with pembrolizumab monotherapy had a complete or partial response. The most common AE was pyrexia (n=5). Conclusion: Intratumoral ulevostinag (±pembrolizumab) had manageable toxicity, dose-dependent pharmacokinetics, and evidence of STING activation and target engagement. Combination therapy showed antitumor activity in participants with untreated metastatic or unresectable, recurrent HNSCC.