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

Abstract

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.

Keywords: ERK inhibitor; MEK inhibitor; MK-8353; Selumetinib; Solid tumors; Tolerability.

Conflict of interest statement

Anastasios Stathis: Consultancy services (institution) to Bayer, Eli Lilly; Advisory (institution): Roche, Janssen; institutional research funding: MSD, AstraZeneca, Roche, AbbVie, Pfizer, Bayer, Novartis, ADC Therapeutics, MEI Therapeutics, Loxo Oncology, Philogen.

Anthony W. Tolcher: ABBVIE, Inc, Aclaris Therapeutics, AGENUS, Inc., ASANA BIOSCIENCES, ASCENTAGE, Axlmmune, Bayer, Blu Print Oncology, Daiichi Sankyo, Inc., GILDE HEALTHCARE PARTNERS, HBM PARTNERS, IDEA Pharma, Immuneering, Immunomet Therapeutics, Inc., Impact Therapeutics US, Inc., Karma Oncology B.V., Kirilys Therapeutics, Inc., Lengo Therapeutics, Inc., Link Immunotherapeutics, Mekanistic Therapeutics, Menarini Ricerche, Mersana, NANOBIOTIX, NervianoMedical Sciences S.r.I. (NMS), Nurix Therapeutics, Ocellaris Pharma, Inc. & Eli Lilly, Partner Therapeutics, Pfizer Inc., Qualigen Therapeutics, PIERRE FABRE, Roche, RYVU THERAPEUTICS, Seattle Genetics, SK Life Science, SOTIO Biotechnology Co., Spirea Limited Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd, Transcenta Therapeutics Inc., Trillium Therapeutics Inc., Verastem Oncology, VRISE Therapeutics, Inc., Zentails, ADAGENE, Inc., ARO BIOTHERAPEUTICS, BIOINVENT, Boehringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, ELUCIDA, EMD SERONO/ MERCK KGaA, Hiber Cell, Inc., Ikena Oncology, IMMUNOME, Janssen Global Services, LLC, NBE THERAPEUTICS, Pelican, JAZZ, Pieris Pharma, PYXIS Oncology, Senti Biosciences, Vincerx, ZielBio, Inc., Zymeworks Biopharmaceuticals Inc., MIRATI, Roche.

Judy S.Wang: Consultant fees from BioNTech, Stemline/Menarini, Janssen, Kanaph. Speakers’ Bureau fees from AstraZeneca and Eisai. Research Funding paid to institution only from: Takeda, Medimmune, Genentech, AstraZeneca, El Lilly, Lycera, Pfizer, Checkpoint, Agenus, Jacobio, Evelo, Merck, Jounce, Boehringer Ingelheim, Janssen, Vedanta, H3 Biomedicine, BioNTech, Phoenix Molecular Designs, Bicycle, Qilu Puget Sound, Xencor, Sanofi, Klus, Treadwell, IGM, PureTech, Erasca, Bayer, BioTheryX, Biosplice, NGM, Cullinan, Astellas, BeiGene, Pinoyr, Taiho, Mirati, Hutchinson MediPharma, Stemline, GSK, TopAlliance, Revolution, Relay, StingThera.

Daniel J. Renouf: Consultancy services: Bayer, Roche, Elevation; Research funding: Roche.

Lin-Chi Chen, Tomoko Freshwater, Andrea L. Webber, Tapan Nayak: Employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholders in Merck & Co., Inc., Rahway, NJ, USA.

Leah H. Suttner: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Lillian L. Siu: Advisory Role/Consultation (self): Amgen, Arvinas, AstraZeneca, Coherus, Hoopika, InteRNA, Janpix, Marengo, Medicenna, Navire, Oncorus, Relay, Roche, Seattle Genetics, Tessa, Voronoi. Research Support (institution): Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono/Merck KGaA, GlaxoSmithKline, Intensity Therapeutics, Merck, Novartis, Pfizer, Roche/Genentech, Shattucks, Symphogen. Leadership Role (spouse): Treadwell Therapeutics.

© 2023. The Author(s).

Figures

Fig. 1

(a) Arithmetic mean plasma concentration versus time curves for MK-8353 following oral administration of the combination, (b) arithmetic mean plasma concentration versus time curves for selumetinib following oral administration of the combination, (c) arithmetic mean plasma concentration versus time curves for desmethyl selumetinib following oral administration of the combination, and (d) 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) results in patients treated at a cycle 1, day 1 dose of MK-8353 100 mg + selumetinib 50 mg, MK-8353 150 mg + selumetinib 75 mg, and in patients where the dose reduction occurred before cycle 2, day 4 PET scans. CFB, change from baseline; SD, standard deviation; SUV, standardized uptake value