MK-4830 administered either as a single agent or in combination with pembrolizumab was well tolerated and showed encouraging objective responses in heavily pre-treated patients with advanced solid tumours, according to findings from a phase I dose escalation study presented by Prof. Lillian L. Siu of the Princess Margaret Cancer Centre, University of Toronto in Toronto, Canada at ESMO Virtual Congress 2020.
Prof. Siu described MK-4830 as a novel, first-in-class human IgG4 monoclonal antibody targeting the myeloid-specific anti–immunoglobulin-like transcript 4 (ILT4) receptor. She further explained that MK-4830 catalyses reprogramming of tumour-associated macrophages, thus relieving myelosuppression and enhancing T cell activity.
Prof. 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 tumours; of these 50 patients were treated with MK-4830 monotherapy and 34 received MK-4830 plus pembrolizumab. All patients received intravenous MK-4830 every three 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 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 tumour.
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.
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 one year.
Regarding the dose escalation data, the maximum-tolerated dose was not reached and no dose-limiting toxicities occurred.
Any-grade adverse events (AEs) were consistent with those reported for pembrolizumab.
MK-4830 demonstrated a good safety profile. The majority of the treatment-related AEs 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 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 MK-4830 in patients with advanced solid tumours.
This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
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.