Intratumoral or Subcutaneous MK-2118, a Noncyclic Dinucleotide STING Agonist, with or without Pembrolizumab, for Advanced or Metastatic Solid Tumors or Lymphomas.

Abstract

Purpose: We evaluated the noncyclic dinucleotide stimulator of IFN genes agonist MK-2118 ± pembrolizumab in participants with advanced solid tumors or lymphomas.

Patients and methods: This first-in-human study (NCT03249792) enrolled participants with refractory, advanced solid tumors or lymphomas. Participants received intratumoral (IT) MK-2118 100 to 20,000 μg (arm 1), IT MK-2118 900 to 15,000 μg plus intravenous (IV) pembrolizumab 200 mg every 3 weeks (arm 2), or subcutaneous (SC) MK-2118 5,000 to 150,000 μg plus IV pembrolizumab 200 mg every 3 weeks (arm 4); arm 3 (visceral injection of MK-2118) was not pursued. IT dosing used an accelerated titration design and modified toxicity probability interval method; SC dosing (arm 4) was started subsequent to arms 1 and 2. The primary objectives were safety/tolerability. MK-2118 pharmacokinetics was a secondary endpoint; objective responses and biomarkers were exploratory endpoints.

Results: A total of 140 participants were enrolled (arm 1, n = 27; arm 2, n = 57; arm 4, n = 56). Grade 3/4 treatment-related adverse events occurred in 22%, 23%, and 11% of participants, respectively, but no maximum tolerated dose was identified up to MK-2118 20,000, 15,000, and 150,000 μg across the three arms. Dose-dependent increases in MK-2118 systemic exposure were observed following IT and subcutaneous administration. Objective responses were seen in 0%, 6%, and 4% of participants, respectively. IT MK-2118 led to dose-dependent changes in stimulator of interferon genes-based blood RNA expression levels, IFNγ, IFNγ-induced protein 10, and IL6; SC MK-2118 did not generate dose-related immune responses.

Conclusions: IT MK-2118 ± pembrolizumab and SC MK-2118 plus pembrolizumab had manageable toxicity and limited antitumor activity. IT but not SC administration demonstrated systemic immune effects.