Abstract 1280: Preclinical and Clinical Evidence for MEK Pathway Inhibition by GDC-0973 using FDG-PET

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Abstract Inhibitors of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) can cause potent growth arrest leading to tumor stasis or even regression, especially in BRAF mutant tumors. Seeking a pharmacodynamic marker of drug action, the effect of MEK inhibition on FDG PET signals was studied in rodent xenograft models using responsive and non-responsive cell lines. Colo205, HCT116, and A375 tumors showed substantial (30-50 %) signal (FDG flux, Ki, measured by a Patlak analysis) decreases within 72 h of beginning MEK inhibition and a rebound to baseline signal within 72 h of discontinuing treatment. BT474 tumors showed no effect. In MEK responsive tumors immunohistochemistry showed that glucose transporter GLUT1 redistributes away from the plasma membrane during treatment, which may explain the FDG PET findings. Fluorothymidine (FLT) uptake is also modulated by MEK inhibition, but the relative availability of clinical FDG PET centers and the robust preclinical results suggested the use of FDG PET, and not FLT PET, in clinic. FDG PET was implemented at all 4 Phase 1 study sites according to a standardized scanning charter. Scans were acquired at screening, at days 10-14 of cycle 1 (steady state drug concentration) and at days 26-28 of cycle 1 (trough drug concentration). Patients with RAS or RAF mutant tumors were treated at GDC-0973 MTD on the 21/7 and 14/14 dosing schedules. CT scans were acquired just prior to cycle 3 (∼ day 56) for response assessment. PET images were collected and read centrally. Up to 5 hypermetabolic lesions were assessed for mean and maximum standardized uptake value (SUV). A decrease of more than 20% in mean (across lesions) percentage change-from-baseline in SUVmax was considered a partial metabolic response (PMR). Compliance with the scanning guidelines across sites was generally good. Out of a total of 23 patients from both cohorts with PET scans read to date, 7 patients appeared to show a temporal profile of decreased FDG uptake at steady state with a rebound towards baseline at trough, mirroring the preclinical findings. Of 17 patients in the 21/7 MTD cohort whose PET scans were measured, 9 patients (∼53%) demonstrated a PMR at least one timepoint during cycle 1. Two of these patients demonstrated a PR per CT at 2 months (first tumor assessment) and also showed a robust PET response at both timepoints (Patient 1: -55% and -61% respectively; Patient 2: -63% and -53%). In addition, 2 other patients with a PMR at one or both timepoints had stable disease for at least 5 months. Of 6 patients in the 14/14 MTD cohort with PET scans read, 5 patients (83%) demonstrated a PMR at least one timepoint. Taken together, the preclinical PET evidence for a mechanistic effect of MEK inhibition on tumor glucose metabolism combined with the significant proportion of patients demonstrating PMR in this phase 1 study are consistent with hypothesis that GDC-0973 is achieving pathway modulation when given as single agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1280. doi:10.1158/1538-7445.AM2011-1280