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, coadministration of cobimetinib and vemurafenib resulted in increased apoptosis in 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.

COTELLIC is a kinase inhibitor indicated: For the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. As a single agent for the treatment of adult patients with histiocytic neoplasms.

Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of COTELLIC with vemurafenib for patients with melanoma. The recommended dose is 60 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take COTELLIC with or without food.

Unresectable or Metastatic Melanoma: Most common adverse reactions for COTELLIC (≥20%) are diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. The most common (≥5%) Grade 3-4 laboratory abnormalities are increased GGT, increased CPK, hypophosphatemia, increased ALT, lymphopenia, increased AST, increased alkaline phosphatase, hyponatremia. Histiocytic neoplasms: Most common adverse reactions (≥20%) are acneiform dermatitis, diarrhea, infection, fatigue, nausea, edema, dry skin, maculopapular rash, pruritus, dyspepsia, vomiting, dyspnea and urinary tract infections. The most common (≥5%) grade 3-4 lab abnormalities include: Hyponatremia, increased blood creatine phosphokinase, hypokalemia, increased blood creatinine, increased AST, hypocalcemia, lymphopenia, leukopenia, anemia

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New primary malignancies, cutaneous and non-cutaneous: Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose of COTELLIC. Hemorrhage: Major hemorrhagic events can occur with COTELLIC. Monitor for signs and symptoms of bleeding. Cardiomyopathy: The risk of cardiomyopathy is increased in patients receiving COTELLIC with vemurafenib compared with vemurafenib as a single agent. The safety of COTELLIC has not been established in patients with decreased left ventricular ejection fraction (LVEF). Evaluate LVEF before treatment, after one month of treatment, then every 3 months thereafter during treatment with COTELLIC. Severe Dermatologic Reactions: Monitor for severe skin rashes. Interrupt, reduce, or discontinue COTELLIC. Serous Retinopathy and Retinal Vein Occlusion: Perform an ophthalmological evaluation at regular intervals and for any visual disturbances. (See Full Prescribing Information.)