title: A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors.
abstract: Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.
authors.affiliation: David Geffen School of Medicine, UCLA, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA, 90404, USA. lrosen@mednet.ucla.edu.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.affiliation: Yale University, New Haven, CT, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.affiliation: David Geffen School of Medicine, UCLA, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA, 90404, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Goldman
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Weise
authors.affiliation: Stanford University, Stanford, CA, USA.
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Adjei
authors.affiliation: Exelixis, Inc., South San Francisco, CA, USA.|Baxalta, Cambridge, MA, USA.
authors.forename: Salim
authors.initials: S
authors.lastname: Yazji
authors.affiliation: Exelixis, Inc., South San Francisco, CA, USA.|Arvinas, New Haven, CT, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Shen
authors.affiliation: Exelixis, Inc., South San Francisco, CA, USA.|Nektar Therapeutics, San Francisco, CA, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Johnston
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Hsin-Ju
authors.initials: HJ
authors.lastname: Hsieh
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Iris T
authors.initials: IT
authors.lastname: Chan
authors.affiliation: Stanford University, Stanford, CA, USA.
authors.forename: Branimir I
authors.initials: BI
authors.lastname: Sikic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001384:Azetidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; C117307:KRAS protein, human; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C482128:MAP2K2 protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); C574276:cobimetinib
keywords: BRAF; Cobimetinib; MEK inhibitor; Melanoma; Phase I