Abstract
MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts (PDX). To translate these results, we conducted a NCI CTEP-approved multicenter Phase I/IB trial (NCT02188264) of the combination of selumetinib and CsA.
Patients with advanced solid malignancies were treated with the combination of oral selumetinib and CsA in the dose escalation phase followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib “run-in” to evaluate FZD2 biomarker upregulation and RAS-WT and RAS-MT stratification to identify any potential predictors of efficacy.
Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities - Grade 3 hypertension, rash and increased creatinine were reported. The maximum tolerated dose was selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. RAS stratification did not identify any differences in response between RAS-WT and RAS-MT cancers. Two partial responses (PR), 18 stable disease (SD), and 10 progressive disease (PD) responses were observed.
Combination selumetinib and CsA is well-tolerated with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation.
