Abstract LB-89: Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study in patients with advanced solid tumors
Authors: Bendell Johanna , LoRusso Patricia , Kwak Eunice , Pandya Susan , Musib Luna , Jones Cheryl , De Crespigny Alex , Belvin Marcia , McKenzie Meghan , Gates Mary R. , Chan Iris , Shapiro Geoffrey 
Published: July 2012

Abstract
Introduction: The RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling pathways are both deregulated in multiple tumor types. Therefore, targeting both pathways may be more efficacious than targeting either pathway alone. GDC-0973 is a novel, potent, selective, MEK1/2 inhibitor. GDC-0941 is a novel, potent, highly-specific, Class I PI3K inhibitor. In single agent Phase 1 trials, both GDC-0973 and GDC-0941 have demonstrated suitable tolerability and PK properties. In preclinical models, concurrent administration of GDC-0973 and GDC-0941 has shown improved efficacy in combination when compared to efficacy of either agent alone.
Methods: A phase Ib dose-escalation study using a 3+3 design in patients (pts) with advanced solid tumors was initiated to evaluate the safety and PK of oral combination dosing of GDC-0973 and GDC-0941. Pts received once daily GDC-0973 and GDC-0941 on a 21-day on/7-day off (21/7) schedule. A unique dose escalation schema allowed for increasing the dose level of each single agent independently. GDC-0973 and GDC-0941 PK samples were collected following first and last doses of combination dosing in Cycle 1. Serial FDG-PET scans were obtained at baseline, Cycle 1 steady state, and Cycle 2 trough drug concentrations.
Results: Twenty-seven pts have been enrolled in six cohorts on a 21/7 schedule. One pt in Cohort 4 (40 mg GDC-0973 + 100 mg GDC-0941) had a DLT of Grade 3 lipase elevation without clinical symptoms, which resolved with study drug interruption. One pt in Cohort 5 (40 mg GDC-0973 + 130 mg GDC-0941) had a DLT of Grade 4 CPK elevation. The common adverse events attributed to GDC-0973 and/or GDC-0941 were diarrhea (90%; all G1/2), fatigue (61%: 50% G1/2, 11% G3), nausea (61%; all G1/2), rash (50%; 45% G1/2, 5% G3), vomiting (33%; all G1/2), decreased appetite (17%; all G1/2), and dysgeusia (17%; all G1/2). Preliminary analysis indicates PK of GDC-0941 and GDC-0973 are not altered when administered in combination. 6 of 15 pts with PET scans read to date demonstrated a partial metabolic response (&gt; 20% decrease in mean % change-from-baseline SUVmax) at one or more timepoints. Decreases in RECIST measurable target lesions were seen in 5 pts: 2 melanoma (−75%, BRAF wt; −27%, BRAF mut), 1 prostate cancer (−21%), and 2 KRAS mutant NSCLC (−18%; −13%). 3 pts (1 KRAS mut NSCLC and 2 BRAF mut melanoma) had prolonged stable disease &gt; 6 months.
Conclusions: To date, clinical combination dosing of the MEK inhibitor GDC-0973 with the Class I PI3K inhibitor GDC-0941 is generally well tolerated, with PK and toxicities similar to those observed in the single agent GDC-0973 and GDC-0941 Phase 1 trials. There are early signs of anti-tumor activity. Dose escalation is continuing and updated data will be presented.
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 LB-89. doi:10.1158/1538-7445.AM2011-LB-89