AVUTOMETINIB POTASSIUM; DEFACTINIB HYDROCHLORIDE

　　【Indications】

　　This product is a combination pack of avutometinib capsules and defactinib tablets,both of which are kinase inhibitors.It is indicated for the treatment of adult patients with recurrent low-grade serous ovarian cancer(LGSOC)harboring KRAS mutations who have received prior systemic therapy.

　　【Recommended Dosage】

　　Avutometinib capsules:

　　The recommended dose is 3.2 mg orally twice weekly(on Day 1 and Day 4 of each week).Dosing is given for the first 3 weeks of each 4-week treatment cycle,and continued until disease progression or unacceptable toxicity occurs.

　　Defactinib tablets:

　　The recommended dose is 200 mg orally twice daily.Dosing is given for the first 3 weeks of each 4-week treatment cycle,and continued until disease progression or unacceptable toxicity occurs.

　　【Adverse Reactions】

　　The most common adverse reactions(incidence≥25%,including laboratory abnormalities)are:

　　Elevated creatine phosphokinase,nausea,fatigue,elevated aspartate aminotransferase,rash,diarrhea,musculoskeletal pain,edema,decreased hemoglobin,elevated alanine aminotransferase,vomiting,elevated blood bilirubin,elevated triglycerides,decreased lymphocyte count,abdominal pain,dyspepsia,acneiform dermatitis,vitreoretinal disorders,elevated alkaline phosphatase,stomatitis,pruritus,visual impairment,decreased platelet count,constipation,dry skin,dyspnea,cough,urinary tract infection,and decreased neutrophil count.

　　【Pharmacological Action】

　　Avutometinib

　　Avutometinib is a MEK1 inhibitor.It induces the formation of inactive RAF/MEK complexes and blocks the phosphorylation of MEK1/2 by RAF.Both RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK(MAPK)pathway.Avutometinib inhibits the phosphorylation of MEK1/2 and ERK1/2 as well as cell proliferation in tumor cell lines carrying KRAS mutations.Treatment of cancer cells with avutometinib results in elevated levels of phosphorylated focal adhesion kinase(FAK).

　　Defactinib

　　Defactinib is an inhibitor of FAK and proline-rich tyrosine kinase 2(Pyk2),both members of the FAK family of non-receptor tyrosine kinases.Defactinib suppresses FAK autophosphorylation in cancer cells both in vitro and in mouse xenograft models.

　　The combination of avutometinib and defactinib enhances the inhibitory effect on cell proliferation in vitro,and augments anti-tumor activity in mouse tumor models including LGSOC.

　　【Storage】

　　Store avutometinib capsules and defactinib tablets in their original containers under refrigeration at 2°C to 8°C(36°F to 46°F).