Clinical combination of the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study testing daily and intermittent dosing schedules in patients with advanced solid tumors.

Developmental Therapeutics - Experimental Therapeutics
Session Type and Session Title: 
Oral Abstract Session, Developmental Therapeutics - Experimental Therapeutics
Abstract Number: 


J Clin Oncol 29: 2011 (suppl; abstr 3005^)
G. Shapiro, P. LoRusso, E. L. Kwak, J. M. Cleary, L. Musib, C. Jones, A. de Crespigny, M. Belvin, M. McKenzie, M. R. Gates, I. T. Chan, J. C. Bendell; Dana-Farber Cancer Institute, Boston, MA; Karmanos Cancer Institute, Detroit, MI; Division of Hematology and Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Genentech Inc., South San Francisco, CA; Sarah Cannon Research Institute, Nashville, TN

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures


Background: The RAS/RAF/MEK and PI3K/AKT signaling pathways are both deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either alone when these agents are dosed either continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral combination dosing of GDC-0973 and GDC-0941. Pts received once daily (QD) GDC-0973 + GDC-0941 on a 21 day on/7 day off (21/7) schedule or intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 QD on a 21/7 schedule. Initial doses were 20 mg GDC-0973 + 80 mg GDC-0941 on 21/7 schedule; 100 mg GDC-0973 + 130 mg GDC-0941 on intermittent schedule. Serial plasma PK samples, FDG-PET and CT scans were obtained. Results: 30 pts have enrolled - 27 pts in 6 cohorts on 21/7 schedule; 3 pts on intermittent schedule. DLTs were grade 3 lipase (n=1) and grade 4 CPK elevation (n=1). Adverse events related to study drug combination 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-0973 or GDC-0941 are not altered when dosed in combination. 6 of 15 pts had an FDG-PET partial metabolic response at one or more timepoints. Decreases in RECIST measurable target lesions were seen in 5 pts: 2 with melanoma (-75%; -27%), 1 prostate cancer (-21%), and 2 NSCLC (-18%; -13%). 3 pts had prolonged stable disease > 6 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase I trials. There are early signs of anti-tumor activity. Dose escalation on both schedules continues and updated data will be presented.