Cobimetinib (GDC-0973, RO5514041, COTELLIC®)

Agent Description

Cobimetinib fumarate is a kinase inhibitor. The chemical name is (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone hemifumarate. It has a molecular formula C₄₆H₄₆F₆I₂N₆O₈ (2 C₂₁H₂₁F₃IN₃O₂ • C₄H₄O₄) with a molecular mass of 1178.71 as a fumarate salt. Cobimetinib is a fumarate salt appearing as white to off-white solid and exhibits a pH dependent solubility. Cobimetinib tablets are supplied as white, round, film-coated 20 mg tablets for oral administration, debossed on one side with “COB”. Each 20 mg tablet contains 22 mg of cobimetinib fumarate, which corresponds to 20 mg of the cobimetinib free base. The inactive ingredients of are: Tablet Core: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate. Coating: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc.

Mechanism of Action

Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase(MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines expressing BRAF V600E, cobimetinib inhibited tumor cell growth.

Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, co-administration of cobimetinib and vemurafenib resulted in increased apoptosis in 12 vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model.

Classification

MEK1/2 inhibitor

Molecular Targets

MEK1/2

Monograph

Approved Indications: Cobimetinib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.

Package insert: https://www.gene.com/download/pdf/cotellic_prescribing.pdf

Studies of Interest

Cobimetinib plus atezolizumab is being evaluated (planned/ongoing) across a broad array of advanced malignancies, including lung, colorectal, pancreas, melanoma (BRAFwt), cutaneous squamous cell (SCC), bladder, kidney (RCC), liver, head/neck SCC, ovarian cancer (platinum-refractory), breast cancer, and prostate (castrate-resistant).

Areas of Interest:

Combinations of cobimetinib +/- atezolizumab with novel targeted therapy (kinase/epigenetic, etc) or immune therapy that further optimize immune response and overcome putative mechanisms of resistance.

Not supported:

Cobimetinib monotherapy, cobimetinib combinations with PI3K/AKT inhibitors

Information collaborator would like included in investigator proposals

N/A

Genentech supports non-clinical research proposals through a separate mechanism. Please visit https://www.gene.com/gene/reagents-program/reagents-program.jsp if you wish to submit a request for a Genentech agent for non-clinical work.