A First-in-Human, Phase I Trial of MK-6598, an Inhibitor of the Immune Checkpoint IL4I1, With or Without Pembrolizumab for Advanced Solid Tumors

Purpose: Interleukin 4 induced 1 (IL4I1) is an immunometabolic enzyme with an immunosuppressive role in the tumor microenvironment. High IL4I1 expression is associated with suppressed antitumor immunity and enhanced metastasis. MK-6598 is a novel, small-molecule inhibitor of IL4I1. This first-in-human study evaluated MK-6598 with or without pembrolizumab in previously treated advanced solid tumors (NCT05594043). Patients and methods: Participants received prespecified, escalating doses of MK-6598 (50, 125, 250, and 500 mg) orally once daily with or without pembrolizumab 200 mg intravenously every 3 weeks. Primary objectives were safety and tolerability. Secondary objectives included the pharmacodynamics of MK-6598; tertiary/exploratory objectives included efficacy endpoints and response biomarker analyses. Results: Thirty-nine participants were enrolled (MK-6598, n=20; MK-6598 plus pembrolizumab, n=19). MK-6598 monotherapy dose escalation was completed with no dose-limiting toxicities (DLTs). Three DLTs occurred in the MK-6598 plus pembrolizumab arm (grade 3 maculopapular rash, n=1 [MK-6598 50 mg]; grade 3 Stevens-Johnson syndrome, n=1 [MK-6598 250 mg]; grade 1 fever and grade 1 influenza-like illness leading to dose delay, n=1 [MK-6598 250 mg]). No fatal treatment-related adverse events occurred. Tumor phenylpyruvate concentrations, per on-treatment biopsy, decreased across all dose levels. Higher tumor IL4I1 expression was associated with higher baseline phenylpyruvate concentration and larger decreases in phenylpyruvate concentration from baseline to day 1 of cycle 2. There were no confirmed responses per RECIST version 1.1 by investigator assessment in either cohort. Conclusions: MK-6598 had a manageable safety profile and demonstrated target engagement when given as monotherapy or in combination with pembrolizumab but had limited antitumor activity.