Intratumoral or Subcutaneous MK-2118, a Non-Cyclic Dinucleotide STING Agonist, With or Without Pembrolizumab for Advanced or Metastatic Solid Tumors or Lymphomas.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Jason J Luke, Randy F Sweis, J Randolph Hecht, Reva Schneider, Mark N Stein, Talia Golan, Timothy A Yap, Anuradha Khilnani, Mo Huang, Runchen Zhao, Thomas Jemielita, Sandip Pravin Patel

TLDR

  • The study evaluated the safety and efficacy of MK-2118 ± pembrolizumab in patients with advanced solid tumors or lymphomas and found that IT administration led to dose-dependent immune responses and antitumor activity.

Abstract

We evaluated the non-cyclic dinucleotide stimulator of interferon genes agonist MK-2118 ± pembrolizumab in patients with advanced solid tumors or lymphomas. This first-in-human study (NCT03249792) enrolled patients with refractory, advanced solid tumors or lymphomas. Patients received intratumoral (IT) MK-2118 100-20,000 µg (arm 1), IT MK-2118 900-15,000 µg plus intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W; arm 2), or subcutaneous (SC) MK-2118 5000-150,000 µg plus IV pembrolizumab 200 mg Q3W (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. Primary objectives were safety/tolerability. MK-2118 pharmacokinetics were a secondary endpoint; objective responses and biomarkers were exploratory endpoints. 140 patients 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 patients, respectively, but no maximum tolerated dose was identified up to MK-2118 20,000, 15,000, and 150,000 µg across the 3 arms. Dose-dependent increases in MK-2118 systemic exposure were observed following IT and SC administration. Objective responses were seen in 0%, 6%, and 4% of patients, respectively. IT MK-2118 led to dose-dependent changes in STING-based blood RNA expression levels, interferon-gamma, interferon-gamma‒induced protein 10, and interleukin-6; SC MK-2118 did not generate dose-related immune responses. 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.

Overview

  • The study evaluated the non-cyclic dinucleotide stimulator of interferon genes agonist MK-2118 ± pembrolizumab in patients with advanced solid tumors or lymphomas.
  • The study aimed to assess the safety, tolerability, and pharmacokinetics of MK-2118, as well as its ability to induce systemic immune responses.
  • The study enrolled 140 patients across four arms, with different dosing regimens of MK-2118 and pembrolizumab.

Comparative Analysis & Findings

  • The study found that IT administration of MK-2118 led to dose-dependent increases in systemic exposure and immunological responses, including changes in blood RNA expression levels and cytokine production.
  • In contrast, SC administration of MK-2118 did not generate significant immune responses and had limited systemic exposure.
  • The study found that the combination of IT MK-2118 and pembrolizumab had manageable toxicity and limited antitumor activity, while SC MK-2118 plus pembrolizumab had limited toxicity and antitumor activity.

Implications and Future Directions

  • The study's findings suggest that IT administration of MK-2118 may be a more effective approach for inducing systemic immune responses and antitumor activity.
  • Future studies should investigate the optimal dosing and combination regimens of MK-2118 and pembrolizumab for different patient populations and tumor types.
  • The study's results also highlight the importance of careful monitoring and management of toxicities associated with IT administration of MK-2118.
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