A phase 1, first-in-human study of DS5361, a small-molecule, nonsense-mediated mRNA decay (NMD) inhibitor in patients with advanced/metastatic solid tumors (parts 1 and 2).

TPS2680 Background: Despite the profound impact of immune checkpoint inhibitors (ICIs) on the treatment of patients with advanced or metastatic solid tumors, only a small proportion of patients experience meaningful responses, underscoring the need for novel therapies to maximize clinical benefit. High tumor mutational burden (TMB-H) and high microsatellite instability (MSI-H) are associated with improved efficacy of ICIs due to an increase in neoantigens, tumor-specific peptides displayed on tumor cell surfaces that are critical for antitumor immune responses. mRNAs harboring premature termination codons, including neoantigenic transcripts derived from frameshift mutations, are recognized and degraded by NMD. DS5361 is a potentially first-in-class, orally available, small-molecule inhibitor targeting the serine/threonine kinase SMG1, a key component of the NMD mechanism. DS5361 is designed to activate antitumor immunity by increasing neoantigen expression and, when administered in combination, to enhance ICI efficacy. Methods: DS5361-061 (NCT07182591) is a Phase 1, first-in-human, open-label, multicenter study (N≈66 for Parts 1 and 2) of DS5361 as monotherapy (Part 1) and in combination with pembrolizumab (Part 2). Patients must be adults, have measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1), and have an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with advanced or metastatic TMB-H and/or MSI-H solid tumors who are unable to tolerate standard treatment or have disease that is refractory to standard treatment, or for which no such treatment is available, will be enrolled across both parts. The primary objectives in Parts 1 and 2 (dose escalation) are to evaluate the safety and tolerability, and determine the maximum tolerated dose, of DS5361 as monotherapy in Part 1 and in combination with pembrolizumab in Part 2, and/or determine the recommended dose(s) for expansion in combination with pembrolizumab (Part 2 only). Safety endpoints include dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints include objective response, disease control, and duration of response, all assessed by the investigator per RECIST 1.1, as well as pharmacokinetics. Enrollment is ongoing. Clinical trial information: NCT07182591 .