A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor.
BACKGROUND
Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer.


METHODS
Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples.


RESULTS
Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial).


CONCLUSIONS
Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.
Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA.
Johanna C
JC
Bendell
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit Number: 426, Room Number: FC10.3062, Houston, TX 77030, USA.
Milind
M
Javle
Department of Internal Medicine, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA.
Tanios S
TS
Bekaii-Saab
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA.
Richard S
RS
Finn
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA.
Zev A
ZA
Wainberg
Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 2825 Santa Monica Boulevard, Baltimore, MD 90404, USA.
Daniel A
DA
Laheru
Division of Medical Oncology, University of Colorado School of Medicine, 12801 East 17th Avenue, RC1 South, Room 8123, Aurora, CO 80045, USA.
Colin D
CD
Weekes
Department of Medicine, Oncology Division, Washington University, School of Medicine, 14th Floor Northwest Tower, Division of Oncology, Campus Box 8056, 660 South Euclid Ave, St Louis, MO 63110, USA.
Benjamin R
BR
Tan
Department of Hematology/Oncology, Henry Ford Health System, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
Gazala N
GN
Khan
Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, SPC 5912, Ann Arbor, MI 48109, USA.
Mark M
MM
Zalupski
Drug Development Program, Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA.
Jeffrey R
JR
Infante
Drug Development Program, Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN 37203, USA.
Suzanne
S
Jones
Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA.
Kyriakos P
KP
Papadopoulos
Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA.
Anthony W
AW
Tolcher
Clinical Development, Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
Renae E
RE
Chavira
Clinical Development, Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
Janna L
JL
Christy-Bittel
Clinical Development, Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
Emma
E
Barrett
Clinical Research, South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX 78229, USA.
Amita
A
Patnaik
D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
D001562:Benzimidazoles; C581313:binimetinib; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D018631:ras Proteins