Combination of the STING Agonist MIW815 (ADU-S100) and PD-1 Inhibitor Spartalizumab in Advanced/Metastatic Solid Tumors or Lymphomas: An Open-Label, Multicenter, Phase Ib Study

Abstract

Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas.

Patients and methods: Patients were treated with weekly intratumoral injections of MIW815 (50-3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks.

Results: Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity.

Conclusions: The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.

Figure 1.

Best percentage change from baseline in target lesions in weekly (A) and monthly (B) treatment schedule, and in injected vs. sum of target lesions in patients treated weekly (C) and monthly (D) with MIW815 and spartalizumab per RECIST v1.1 or Cheson 2014 criteria, according to MIW815 dose level. Note: One patient diagnosed with melanoma did not have any target lesions per RECIST v1.1 at baseline, so was not evaluable for best % change, but the patient had a confirmed PR based on nontarget lesion response.

Figure 2.

Best percentage change from baseline in target lesion with corresponding CD8 and PD-L1 expression by MIW815 dose level in patients with TNBC (A) and melanoma (B). Note: PD-L1% positive immune cells (A) were assessed using the SP142 assay; PD-L1 Mel Score (B) was measured using the Dako 22C3 assay. In B, 1 patient diagnosed with melanoma did not have any target lesions per RECIST v1.1 at baseline, so was not evaluable for best % change, but the patient had a confirmed PR based on nontarget lesion response.

Figure 3.

Plasma concentration. A, MIW815 plasma concentration–time profile according to MIW815 dose level. B, Change in IFNβ plasma concentration from pre-MIW815 dose to 6-hour post-dose vs. MIW815 AUC_last. Note: Combined 6-hour post-dose change from pre-dose for Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 3 Day 1 are shown. AUC_last, AUC from time zero to time of last measurable concentration; CR, complete response; NCR/NPD, no complete response/no progressive disease; PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown.