Abstract CT074: Discovery and preliminary clinical findings of MK-6598, a potent and selective inhibitor of the immune checkpoint IL4I1

Abstract Therapeutic blockade of PD-1:PD-L1/L2 interactions is effective in many cancers, particularly those with pre-existing inflammation and T cell infiltration. We identified a correlation between high interleukin 4 induced 1 (IL4I1) gene expression within the tumor micorenvironment (TME) of tumors and response to the PD-1 inhibitor pembrolizumab (pembro). IL4I1 protein is secreted by myeloid and tumor cells into the extracellular TME where it generates hydrogen peroxide upon deamination of amino acid substrates, primarily L-phenylalanine to phenylpyruvate. At IL4I1 concentrations similar to those measured in human tumors, hydrogen peroxide generated by IL4I1 is cytotoxic to T cells in vitro and suppresses T cell responses in mixed lymphocyte reactions. These data collectively support an immunosuppressive role of IL4I1 in the TME. Small molecule inhibitory ligands of IL4I1 have not been previously described. Chemical optimization led to the discovery of MK-6598, which has an IC50 of 16 nM against recombinant IL4I1 in a biochemical assay and exhibits a robust PK/PD relationship based on tumor phenylpyruvate concentrations in mouse models. Mixed lymphocyte reactions and ex vivo organoids were used to validate the target and mechanism of action of MK-6598 in preclinical models. The phase 1 MK-6598-001 dose escalation study (NCT05594043) was designed to assess the safety, tolerability, PK, and antitumor activity of MK-6598 administered orally at four doses from 50-500 mg once daily as monotherapy (arm 1) or in combination with pembro 200 mg administered intravenously every 3 weeks in participants (pts) with previously treated advanced solid tumors. 20 pts received MK-6598 alone in arm 1, and 19 received MK-6598 plus pembro in arm 2. Median age was 62 y. Of the 20 tumor types represented, ovarian and colorectal were the most common (n=6 each). There were no dose limiting toxicities (DLTs) in the monotherapy arm and 3 DLTs observed in the pembro combination arm (grade 3 maculopapular rash, grade 3 Stevens-Johnson syndrome [recovered], and delay in dosing due to grade 1 fever). MK-6598 plasma concentrations increased with dose and were above the predicted IC70 for all pts and the predicted IC90 for >80% of pts. Tumor biopsies were performed at baseline and predose at cycle 2 day 1 (C2D1) to quantitatively assess IL4I1 protein and phenylpyruvate by mass spectrometry. Evidence of IL4I1 inhibition was illustrated by reductions in tumor phenylpyruvate at C2D1 in >90% of pts, with reductions >50% observed in >60% of pts. The only response was in a pt with mismatch repair-deficient endometrial cancer that progressed on prior pembro achieved a partial response after crossing over from MK-6598 monotherapy to MK-6598 plus pembro. These data suggest that despite its ability to inhibit IL4I1 protein, MK-6598 has limited antitumor activity as monotherapy or in combination with pembro in pts with previously treated advanced solid tumors. Citation Format: Dagmar Hess, Nicolas Mach, Rahima Jamal, Anastasios Stathis, Steven F. Powell, Markus Joerger, Andrey Loboda, Yao Chen, Stuart Shumway, Erik H. Knelson, Lillian L. Siu. Discovery and preliminary clinical findings of MK-6598, a potent and selective inhibitor of the immune checkpoint IL4I1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT074.