First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors

Abstract

Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m2) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2 given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m2 before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for ≥ 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted.

Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy

“…Selinexor levels were greater than 100nM (44.3 ng/mL) for the first 24 hours post oral dosing with 10 mg/kg (Figure 5B). Similar kinetics have been observed in humans, with serum levels of selinexor dropping below 100nM after approximately 24 hours post oral dosing (35 mg/m 2 ) (17). …”

“…PDL1 surface expression was likewise unchanged. The recommended Phase 2 dosing regimen of selinexor is 60 mg (35.3 mg/m 2 ) given twice weekly (days 1 and 3) (17). This dosing is supported by the optimized dosing regimen that we propose here for maintenance of anti-tumor immunity.…”

“…Selinexor (KPT-330) is a highly specific, slowly reversible, covalent inhibitor of XPO1, and has shown promising results in phase I/II clinical trials of hematologic and solid malignancies (15–17). Selinexor treatment dramatically reduces tumor burden in a variety of both xenograft and syngeneic mouse models (18–23).…”

“…Selinexor treatment dramatically reduces tumor burden in a variety of both xenograft and syngeneic mouse models (18–23). Although selinexor is fairly well tolerated, side effects of treatment include fatigue, nausea and thrombocytopenia (17). …”

XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer

“…To investigate this, we used the XPO1 inhibitors KPT-185 and KPT-330 (Selinexor) 10,12,13 (Extended Data Fig. 3a).…”