Phase I dose-escalation study of the safety and pharmacokinetics of PAS-004, a macrocyclic MEK inhibitor, for the treatment of patients with MAPK pathway–driven advanced solid tumors.

3125 Background: PAS-004 is a small molecule allosteric inhibitor of MEK 1/2 and the first macrocyclic structure MEK inhibitor in clinical development. Macrocycles are large cyclic molecules that can bring increased potency, metabolic stability, and oral bioavailability. PAS-004 was developed to reduce metabolic liabilities and overcome the limited exposure and stability of known MEK inhibitors. We report initial results of an ongoing Phase I dose escalation, multicenter study of PAS-004 in monotherapy in patients with advanced refractory solid tumors. Methods: The Phase 1 clinical trial is a multi-center, open-label, dose escalation 3+3 study design to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of PAS-004 in patients with MAPK pathway driven advanced solid tumors with a documented RAS, NF1 or RAF mutation, or patients who have failed BRAF/MEK inhibition (NCT06299839).Eligible pts, ≥18 years with MAPK-driven advanced solid tumors, are being enrolled in dose escalation at 8 different dose cohorts in monotherapy. Results: As of 3 Jan 2025, a total of 9 patients have been enrolled in dose escalation in 3 dose cohorts (2mg, 4mg, and 8mg). 55.6% of the patients were female with a median age of 60 years. Most common tumor types included colorectal (n = 5, 55.56%), pancreatic (n = 2, 22.22%), gastroesophageal (n = 1, 11.11%), and of unknown type (n = 1, 11.11%). Treatment Related Adverse Events (TRAE) were reported in 44.44% of patients. TRAEs were all low grade (n = 7, 100% were Grade 1-2). No Grade 3, 4 or 5 TRAEs were reported. The most common TRAEs were gastrointestinal disorders (n = 4, 57.14%), dehydration (14.29%), arthralgia (14.29%) and urinary incontinence (14.29%). No rash was observed in any dose cohort. No dose limiting toxicities were detected, and the MTD has not been reached. Preliminary PAS-004 PK analysis suggests linear PK with estimated t1/2 of 70h, Cmax/Cmin ratio of 1.4 at steady state, achieving potentially sufficient exposures for target engagement at the highest dose tested. In the efficacy evaluable population (n = 6), early response evaluation reveals stable disease (SD) by RECIST 1.1 was observed in 2 patients, with progression free survival of up to 159 days and overall survival of up to 253 days. Conclusions: To date, PAS-004 is shown to be a safe and well-tolerated novel MEK inhibitor, with dose-dependent PK profile and preliminary clinical activity in monotherapy in patients with heavily pre-treated refractory solid tumors. PAS-004 has the potential to achieve prolonged target inhibition and once-daily dosing (QD) due to its long half-life and low Cmax to Cmin ratio. These findings provide a compelling rationale to continue to test PAS-004 into clinical trials for the treatment of MAPK-driven opportunities. Clinical trial information: NCT06299839 .