Preliminary results from a first-in-human, phase I/II study of VLS-1488, an oral KIF18A inhibitor, in patients with advanced solid tumors.

3012 Background: VLS-1488 is an oral small molecule inhibitor of KIF18A, a mitotic kinesin protein important for successful division of cancer cells with chromosomal instability (CIN) but not required for mitosis in normal cells. Preclinical studies of VLS-1488 showed dose-dependent inhibition of tumor growth in CIN models. Methods: VLS-1488-2201 is a phase I/II study of patients (pts) with advanced solid tumors consisting of two parts, Dose Escalation and Dose Expansion. During Dose Escalation, a Bayesian Optimal Interval design was utilized to enroll pts to dose escalation cohorts with additional pts enrolled to backfill cohorts at dose levels (DLs) that did not meet de-escalation/elimination rules. Primary objective was to assess safety/tolerability of VLS-1488 at various DLs to determine the Maximum Tolerated Dose (MTD). Secondary objectives included evaluating preliminary efficacy and pharmacokinetics (PK). Eligible pts had exhausted standard of care treatments and had measurable disease per RECIST v1.1. Pts received VLS-1488 once daily, orally for 28-day cycles until disease progression, unacceptable toxicity or other stopping criteria. Results: 52 pts (ITT) were enrolled across 5 DLs including 50mg (n = 4), 100mg (n = 12), 200mg (n = 14), 400mg (n = 12) and 800mg (n = 10). Tumor types were high grade serous ovarian (HGSOC; n = 20), colorectal (n = 14), triple negative breast (n = 7), squamous lung (n = 3), endometrial (n = 3), ovarian carcinosarcoma (n = 2), esophageal (n = 2) and bladder (n = 1). The median number of prior lines was 4 (range 1-8). As of data cutoff, 52 pts (100%) received >1 dose of VLS-1488. No dose-limiting toxicities (as assessed during the first 28 days) were observed and MTD was not reached. Treatment-related AEs (TRAEs) occurred in 22 pts (42%), with fatigue (17.3%; G1 13.5%, G2 3.8%), aspartate aminotransferase increased (13.5%; G1 7.7%, G2 1.9%, G3 3.8%) and rash (11.5%; G1 3.8%, G2 1.9%, G3 5.8%) observed in >10% of pts. 6 pts (12%) experienced G3 TRAEs and no > G3 TRAEs were observed. Drug exposures exceeded preclinically defined efficacious thresholds and were approximately dose proportional at analyzed DLs. 41 pts (79%) were evaluable for response per RECIST v1.1. In the 16 HGSOC pts evaluable for response (where the median number of prior lines was 4.5; range 2-8), 3 partial responses (PRs; including 2 pts with sustained PR >24 weeks) and 6 with stable disease (SD; including 4 pts with tumor reductions) were observed across multiple DLs, with 5 pts continuing with study treatment. Conclusions: VLS-1488 was found to be safe and tolerable, with encouraging anti-tumor activity observed in heavily treated HGSOC pts. VLS-1488 will be evaluated further in the Dose Expansion phase of the study. Clinical trial information: NCT05902988 .