A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors

• Published in: Investigational new drugs 2024-10, Vol.42 (5), p.581-589
• Main Authors: Lakhani, Nehal J., Burris, Howard, Miller, Wilson H., Huang, Mo, Chen, Lin-Chi, Siu, Lillian L.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; Cancer therapies; Cell death; Cell growth; Dose-Response Relationship, Drug; Drug dosages; Extracellular signal-regulated kinase; Female; Humans; Immune checkpoint inhibitors; Kinases; Lung cancer; Lung diseases; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Melanoma; Metastasis; Middle Aged; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neoplasms - drug therapy; Oncology; Oral administration; Pembrolizumab; Pharmacology/Toxicology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - therapeutic use; Proteins; Solid tumors; Toxicity; Tumors
• ISSN: 0167-6997; 1573-0646; 1573-0646
• DOI: 10.1007/s10637-024-01461-z

Summary Combining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors.