First-in-Class Anti-Immunoglobulin-Like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1-Resistance Mechanism in Patients With Advanced Solid Tumors.

Abstract

PURPOSE\nIn this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.\n\n\nEXPERIMENTAL DESIGN\nPatients with histologically/cytologically-confirmed advanced solid tumors, measurable disease by RECISTv1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A, B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECISTv1.1, and molecular biomarkers were also evaluated.\n\n\nRESULTS\nOf 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum-tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.\n\n\nCONCLUSIONS\nThis first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent.