Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors

by Selleckchem | Aug 21 2023

Aim: We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors.

Methods: This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologically documented, locally advanced/metastatic solid tumors. MK-8353/selumetinib dose combinations were intended to be investigated in sequence: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Each agent was administered orally BID 4 days on/3 days off in repeating cycles every 21 days. Primary objectives were safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy.

Results: Thirty patients were enrolled. Median (range) age was 61.5 (26-78) years and 93% had received previous cancer therapy. Among 28 patients in the dose-limiting toxicities [DLT]-evaluable population, 8 experienced DLTs: 1/11 (9%) in the MK-8353/selumetinib 100/50-mg dose level experienced a grade 3 DLT (urticaria), and 7/14 (50%) in the 150/75-mg dose level experienced grade 2/3 DLTs (n = 2 each of blurred vision, retinal detachment, vomiting; n = 1 each of diarrhea, macular edema, nausea, retinopathy). The DLT rate in the latter dose level exceeded the prespecified target DLT rate (~30%). Twenty-six patients (87%) experienced treatment-related adverse events (grade 3, 30%; no grade 4/5), most commonly diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Three patients (10%) experienced treatment-related adverse events leading to treatment discontinuation. Best response was stable disease in 14 patients (n = 10 with MK-8353/selumetinib 150/75 mg).

Conclusion: MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed.

Comments:

In this study, the combination of MK-8353 (an inhibitor of extracellular signal-regulated kinase 1/2) and selumetinib (an inhibitor of mitogen-activated extracellular signal-regulated kinase 1/2) was evaluated in patients with advanced solid tumors. The study aimed to determine the safety and tolerability of different dose combinations and establish recommended doses for further investigation in phase 2 trials.

The study was a phase 1b, open-label, dose-escalation trial that enrolled adults with locally advanced or metastatic solid tumors. The dose combinations of MK-8353 and selumetinib that were investigated sequentially were as follows: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Both agents were administered orally twice daily for 4 days followed by a 3-day break in repeating cycles every 21 days.

Thirty patients were enrolled in the study, with a median age of 61.5 years. The majority of patients (93%) had previously received cancer therapy. Among the 28 patients evaluated for dose-limiting toxicities (DLTs), eight patients experienced DLTs. At the 100/50 mg dose level of MK-8353/selumetinib, one patient (9%) experienced a grade 3 DLT (urticaria). At the 150/75 mg dose level, seven patients (50%) experienced grade 2 or 3 DLTs, including blurred vision, retinal detachment, vomiting (two patients each), and diarrhea, macular edema, nausea, and retinopathy (one patient each). The DLT rate at the 150/75 mg dose level exceeded the predefined target rate of approximately 30%.

Treatment-related adverse events occurred in 26 patients (87%), with the most common being diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Grade 3 adverse events were observed in 30% of patients, but no grade 4 or 5 events were reported. Three patients (10%) discontinued treatment due to treatment-related adverse events. The best response observed in the study was stable disease in 14 patients, with the majority (10 patients) occurring in the MK-8353/selumetinib 150/75 mg dose group.

In conclusion, the combination of MK-8353/selumetinib at the 50/25 mg and 100/50 mg dose levels demonstrated acceptable safety and tolerability in patients with advanced solid tumors. However, the 150/75 mg dose level was found to be intolerable due to a high incidence of dose-limiting toxicities. No objective responses were observed in the study. These findings provide important preliminary information for the design of future phase 2 trials investigating the combination therapy.