5869 - Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Metastatic Colorectal Cancer (mCRC)

Background

Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (e.g. p53, IκB), and promotes the translation of eIF4E-bound mRNAs coding oncoproteins (e.g. c-MYC, BCL-2, AR). Inhibition of XPO1 using selinexor, the first-in-human SINE compound, showed anticancer activity in patients (pts) with solid tumors including mCRC. Eltanexor (ELTA), a second-generation SINE compound, showed promising anticancer activity in preclinical models of CRC. Non-clinical and preliminary clinical activity of SINE compounds support the increased sensitivity in KRAS mutant neoplasia. Therefore, ELTA was evaluated in mCRC pts with known KRAS status.

Methods

This was part of a phase 1/2 study (NCT02649790)to determine the safety,preliminary efficacy, and recommended phase 2 dose of ELTA in pts with advanced cancers. Pts with mCRC (≥50% KRAS mutant) in expansion cohorts received once daily oral ELTAfor 5 days per week at 20 (n=7) or 30 (n=23) mg. Response was evaluated by RECIST 1.1 criteria every 28-day cycle.

Results

As of 15 Jul 2018, 23 pts with mCRC (of 30 pts; median prior therapies; 4 and age; 63) were evaluable for efficacy: 18 stable disease (SD; 1 pt with a 20% max tumor reduction) and 5 progressive disease (PD) after 1 mo, with no objective responses. Duration of treatment showed 30% (7/23) SD at 4 mos and 13% (3/23) SD at ≥6 mos. The preliminary median progression free survival (PFS) for all pts was 3.5 mos. The most common treatment-related adverse events (TRAEs) occurring in ≥20% of the population were vomiting (60%; 3% Gr≥3), nausea (50%; 7% Gr≥3), fatigue (40%; 17% Gr≥3), anorexia (30%; no Gr≥3), anemia (27%; 17% Gr≥3), hyponatremia (27%; 23% Gr≥3), and thrombocytopenia (23%; 7% Gr≥3 including the only Gr 4 TRAE observed in mCRC). There was no difference in sensitivity of KRAS wild type or mutant pts.

Conclusions

ELTA is well-tolerated with manageable AEs in mCRC. Even though this was small sample size, ELTA shows promise with a longer median PFS in this heavily treated population when compared to the currently available 3^rdline therapies. Enrollment is complete with plans to initiate Phase 2/3 in late 2019.

Clinical trial identification

NCT02649790

Editorial Acknowledgement