MK-6598: An Investigational IL4I1 Inhibitor - Preclinical and Clinical Evaluation

1. Executive Summary

MK-6598 is an investigational, orally administered small molecule developed by Merck Sharp & Dohme (MSD) as a potent and selective inhibitor of Interleukin-4-Induced Gene 1 (IL4I1).[1] IL4I1 is an enzyme secreted within the tumor microenvironment (TME) that contributes to immune suppression by generating hydrogen peroxide, which is cytotoxic to T cells.[1] The therapeutic rationale for MK-6598 is to reverse this immunosuppression and enhance anti-tumor immune responses.

Preclinical studies demonstrated MK-6598's high potency against IL4I1 (IC50 of 16 nM) and established a pharmacodynamic relationship based on the reduction of tumor phenylpyruvate, a product of IL4I1 activity, in mouse models.[1] These findings supported its progression into clinical trials.

The Phase 1 MK-6598-001 (NCT05594043) study evaluated MK-6598 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.[1] The study confirmed target engagement, with dose-dependent increases in MK-6598 plasma concentrations and significant reductions in tumor phenylpyruvate levels in patients.[1] The monotherapy arm reported no dose-limiting toxicities (DLTs). However, the combination arm with pembrolizumab saw three DLTs, including Grade 3 maculopapular rash and Grade 3 Stevens-Johnson syndrome.[1]

Despite evidence of target inhibition, MK-6598 demonstrated limited antitumor activity in this heavily pre-treated, diverse patient population, both as a monotherapy and in combination with pembrolizumab.[1] The only objective response was a partial response in a patient with mismatch repair-deficient endometrial cancer who had progressed on prior pembrolizumab and received the combination after crossing over from monotherapy.[1]