B109 Background: The RAS, RAF, mitogen-activated protein kinase kinase (MEK) and extracellular signal regulated kinase (ERK) pathway represents a promising therapeutic target. It is activated in several human tumors, often through gain-of-function mutations of RAS and RAF family members that might involve similar downstream dependencies. Since ERK is the only known MEK substrate, MEK inhibition is a key target of this pathway. PD-0325901 is a potent and selective MEK1/2 inhibitor.
Methods: PD-0325901 was administered orally at 1 mg QD, and at 1 to 30 mg BID in the first-in-human phase 1 study. Three dosing schedules were evaluated in 28-day (D) cycles (C): intermittent (3 weeks on/1 week off), continuous (every D), and continuous with breaks (5 D on/2 D off). Serial blood samples were obtained on C1D1 and C1D21 (or C1D19) in 58 patients, and urine samples were collected in intervals on C1D21 in 35 patients. Plasma and urine concentrations of PD-0325901, its carboxylic acid metabolite (PD-0315209), and its S-enantiomer (PD-0326116) were determined. The effect of food on PD-0325901 PK was evaluated in 16 patients. Tumor tissue was sampled at baseline and C1D15 (or C1D19) from 27 patients and assessed by immunohistochemistry (IHC) for pERK modulation. Other biomarker evaluations included: Ki-67, pAKT, and PTEN methylation. Mutational analysis of select regions of BRAF, NRAS, and KRAS genes were also performed. Plasma drug concentrations were also determined at tumor tissue collection.
Results: In general, both Cmax and AUC(0-24) of PD-0325901 increased proportionally with the doses tested. The time to peak plasma concentration occurred within 1-2 hours after administration on an empty stomach, and was delayed for 2-8 hours with a meal. The mean elimination plasma half-life (t1/2) was 8.8 hours. The exposure of PD-0315209 was comparable to that of the parent; the mean ratios of PD-0315209 to PD-0325901 plasma AUC(0-24) were approximately 124% following repeated dosing. The terminal t1/2 of PD-0315209 appeared to be longer than that of the parent drug. About 2.5% of the administered PD-0325901 dose was excreted from urine as unchanged. PD-0325901 suppressed tumor pERK in a dose-dependent trend. Doses ≥ 2mg BID, at which the plasma concentration exceeded the minimum target level based on xenograft mouse models, consistently caused >60% suppression of pERK in tumors. Ki-67 was also reduced in some cases. BRAF and KRAS or NRAS mutations were detected in 20 of 41 cases screened and were mutually exclusive. Fourteen of 30 patients with melanoma had mutations in the BRAF gene, all of which were at the V600E site.
Conclusion: The PK of PD-0325901 was characterized by rapid absorption, with generally dose-proportional increases in Cmax and AUC. PD-0325901 suppresses pERK in tumor tissue. Correlations between mutational status and clinical benefit will be presented.