A First-In-Human Study of the SUMOylation Inhibitor Subasumstat In Patients With Advanced/Metastatic Solid Tumors or Relapsed/Refractory Hematologic Malignancies

Abstract Purpose: Subasumstat (TAK-981) is a first-in-class inhibitor of SUMOylation that can engage innate and adaptive immune responses in tumors by enhancing type I interferon (IFN-I) production. We conducted a phase I/II dose escalation/expansion study (NCT03648372) to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of subasumstat as a single agent in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Patients and Methods: Eligible patients received subasumstat intravenously at escalating doses twice-weekly (BIW, days 1, 4, 8, and 11) or once-weekly (days 1 and 8) in 21-day cycles until disease progression or unacceptable toxicity. Results: A total of 109 patients were enrolled (solid tumors: n = 100; lymphomas, n = 9). In phase I, four patients reported dose-limiting toxicities of grade 3 ALT/AST elevation, pneumonitis, stomatitis, and cognitive disorder; 120 mg BIW was determined as the maximum tolerated dose. The most common adverse events were fatigue (47%), nausea (41%), diarrhea (36%), and pyrexia (36%). Pharmacodynamic analyses demonstrated target engagement and SUMOylation pathway inhibition, induction of an IFN-I-regulated gene signature and cytokine production, and activation of innate and adaptive immune cells. Based on safety, pharmacokinetic, and pharmacodynamic findings, 90 mg BIW was proposed as the recommended phase II dose. Overall, three and 26 patients achieved a partial response and stable disease, respectively. Conclusions: Subasumstat had a manageable safety profile, with evidence of innate and adaptive immune response engagement in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Further studies are needed to determine the role of subasumstat in cancer treatment.