MK-4830—a novel, first-in-class human IgG4 monoclonal antibody targeting the myeloid-specific anti–immunoglobulin-like transcript 4 (ILT4) receptor—administered either as a single agent or in combination with pembrolizumab was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors. These findings from a phase I dose-escalation study were presented by Lillian L. Siu, MD, FRCPC, FASCO, of the Princess Margaret Cancer Centre, University of Toronto, at the ESMO Virtual Congress 2020 (Abstract 524O).
Dr. Siu further explained that MK-4830 catalyzes reprogramming of tumor-associated macrophages, thus relieving myelosuppression and enhancing T-cell activity.
Lillian L. Siu, MD, FRCPC, FASCO
Phase I Study
Dr. Siu and colleagues conducted this first-in-human phase I dose-escalation study of MK-4830 as a single agent and MK-4830 in combination with pembrolizumab. The study enrolled 84 patients with advanced solid tumors; of these, 50 patients were treated with MK-4830 monotherapy and 34 received MK-4830 plus pembrolizumab. All patients received intravenous MK-4830 every 3 weeks 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 three or more lines of therapy.
The primary endpoints of the study were safety and tolerability, while pharmacokinetics served as a secondary endpoint. Exploratory objectives included objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1, evaluation of receptor occupancy, and immune correlates of response in blood and tumor.
Results
Objective responses were observed among these heavily pretreated 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.
Preliminary analysis of efficacy data demonstrated 11 objective responses, with 2 patients achieving 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 1 year.
Regarding the dose-escalation data, the maximum tolerated dose was not reached, and no dose-limiting toxicities occurred.
Any-grade adverse events were consistent with those reported for pembrolizumab. MK-4830 demonstrated a good safety profile. The majority of the treatment-related adverse events 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 receptor occupancy.
Fifteen patients provided pre- and on-treatment biopsies, which enabled a preliminary assessment of the association between receptor occupancy 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 pointed out that durable responses were achieved with MK-4830 monotherapy and in combination with pembrolizumab in heavily pretreated patients, including those who had progressed on prior checkpoint inhibitors. They concluded that these initial data support the further development of MK-4830 in patients with advanced solid tumors.
Disclosure: This study was funded by Merck Sharp & Dohme Corp. For full disclosures of the study authors, visit oncologypro.esmo.org.
