MK-4830, an antibody targeting the myeloid-specific ILT4 receptor, administered either as a single agent or in combination with pembrolizumab (Keytruda®; Merck & Co.) was well tolerated and demonstrated encouraging objective responses in heavily pre-treated patients with advanced solid tumors.
This is the conclusion based on findings from a phase I dose-escalation study presented by professor Lillian L. Siu, MD, FRCPC, a Senior Scientist, Princess Margaret Cancer Centre, Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre at the University of Toronto in Toronto, Canada, during the ESMO Virtual Congress 2020.
In her presentation, Siu described MK-4830 as a novel, first-in-class human IgG4 monoclonal antibody targeting the inhibitory immune checkpoint receptor myeloid-specific anti–immunoglobulin-like transcript 4 (ILT4), a transmembrane protein and inhibitory member of the immunoglobulin-like transcript (ILT) family of proteins.
Siu noted that ILT4 plays a key role in tumor immune evasion. ILT4 is primarily expressed by myeloid cells, including monocytes, macrophages, dendritic cells (DCs) and granulocytes, and certain tumor cells.*
Mechanism of action
Following administration, the anti-ILT4 monoclonal antibody MK-4830 targets and binds to ILT4, which prevents the binding of ILT4 ligands to their receptor and prevents ILT4-mediated signaling. This, in turn, abrogates the immunosuppressive activities of ILT4 in the tumor microenvironment (TME), activates the expression of pro-inflammatory cytokines, including GM-CSF and tumor necrosis factor-alpha (TNFalpha), and enhances a cytotoxic T-lymphocyte (CTL)-mediated anti-tumor immune response.
MK-4830 catalyzes the reprogramming of tumor-associated macrophages, thus relieving myelosuppression and enhancing T cell activity.
Phase I study
Siu and colleagues conducted this first-in-human phase I dose-escalation study (NCT03564691) of MK-4830 as a single agent and MK-4830 in combination with pembrolizumab (200 mg Q3W). The study enrolled 84 patients with advanced solid tumors. The majority of patients enrolled in the study (51%) had received three or more prior lines of therapy.
A total of 50 patients were treated with MK-4830 monotherapy and 34 patients received MK-4830 plus pembrolizumab. All patients received intravenous MK-4830 every three weeks (Q3W) at escalating doses whether MK-4830 was administered alone or with pembrolizumab.
The patients’ median age was 62 years and 50% of them had previously received 3 or more lines of therapy.
The primary endpoints of the study were safety and tolerability while pharmacokinetics served as a secondary endpoint and exploratory objectives included objective response rate per RECIST v1.1, evaluation of receptor occupancy (RO), and immune correlates of response in blood and tumor.
Objective responses were observed among these heavily pre-treated patients, including three patients that had not previously responded to anti–PD-1 therapy, and two that had progressed on prior anti-PD-1 therapy.
A preliminary analysis of efficacy data demonstrated 11 objective responses, with 2 patients achieving a complete response and 9 patients showing partial response. One patient treated with single-agent MK-4830 showed a response. These responses were durable with some patients remaining on treatment for more than one year.
Regarding the dose escalation data, the maximum-tolerated dose (MTD) was not reached and no dose-limiting toxicities occurred.
Adverse events and safety profile
The investigators reported that any-grade treatment-related adverse events (TRAEs) were consistent with those reported for pembrolizumab. Overall, MK-4830 demonstrated a good safety profile. The majority of TRAEs reported by 52% of patients were grades 1 and 2.
Pharmacokinetic analysis showed that MK-4830 achieved steady-state serum pharmacokinetics at Ctrough at the highest dose levels. At these high dose levels, nearly all patients had ≥95% blood RO.
Fifteen patients provided pre- and on-treatment biopsies, which enabled a preliminary assessment of the association between RO and immune cell subsets before and during treatment.
Based upon these preliminary results, the authors were able to conclude that the first-in-class MK-4830 antibody targeting ILT4 was well tolerated both as monotherapy and in combination with pembrolizumab. Furthermore, dose-related evidence of target engagement was observed.
The authors also pointed out that durable responses were achieved with MK-4830 monotherapy and in combination with pembrolizumab in heavily pre-treated patients, including those who had progressed on prior checkpoint inhibitors.
They concluded that these initial data support the further development of monotherapy MK-4830 or therapy in combination with pembrolizumab in patients with advanced solid tumors.
This study was funded by Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co.
* The expansion cohorts of this study include pancreatic adenocarcinoma, glioblastoma, head, and neck squamous cell carcinoma (recurrent or metastatic; PD-L1 positive), advanced NSCLC, and gastric cancer.
Study of MK-4830 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-4830-001) – NCT03564691
Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co.)[Prescribing Information]
 524O – Siu LL, Wang D, Hilton J, et al. Initial results of a phase I study of MK-4830, a first-in-class anti–immunoglobulin-like transcript 4 (ILT4) myeloid-specific antibody in patients (pts) with advanced solid tumors. ESMO Virtual Congress 2020.
Featured image: ESMO 2018. Photo courtesy: © 2020 European Society for Medical Oncology. Used with permission.