Avapritinib

Gastrointestinal Stromal Tumors

Gastrointestinal Stromal Tumors Indicated for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutation 300 mg PO once daily Continue until disease progression or unacceptable toxicity Systemic Mastocytosis Indicated for advanced systemic mastocytosis (AdvSM) AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SMAHN), and mast cell leukemia (MCL) 200 mg PO once daily Continue until disease progression or unacceptable toxicity Indolent Systemic Mastocytosis Indicated for indolent systemic mastocytosis (ISM) 25 mg PO once daily

Renal impairment Mild-to-moderate (CrCl 30-90 mL/mL): No dosage adjustment necessary Severe or end-stage renal disease (CrCl <30 mL/min): Effect on pharmacokinetics unknown

Hepatic impairment Mild [total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 times ULN and any AST or moderate [total bilirubin >1.5 to 3 times ULN and any AST] hepatic impairment: No dosage adjustment necessary Severe (Child-Pugh C) Reduce starting dose GIST: 200 mg PO once daily AdvSM: 100 mg PO once daily SIM: 25 mg PO every other day

Administer on an empty stomach, at least 1 hr before and 2 hr after a meal

Intracranial Hemorrhage: Permanently discontinue for any occurrence of any grade. Cognitive Effects: A broad spectrum of cognitive adverse reactions can occur in patients receiving Avapritinib. In patients with GIST, AdvSM, or ISM depending on the severity, continue Avapritinib at same dose, withhold and then resume at same or reduced dose upon improvement, or permanently discontinue. Photosensitivity: May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception.

Not Classi Pregnancy Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman No data available on use in pregnant women Verify pregnancy status of females of reproductive potential before initiation Contraception Females of reproductive potential: Use effective contraception during treatment and for 6 weeks after the final dose Males with female partners of reproductive potential: Use effective contraception during treatment and for 6 weeks after the final dose Infertility Based on findings from animal studies, may impair fertility for both males and females Animal studies H4 Oral administration of avapritinib to pregnant animals during organogenesis was teratogenic and embryotoxic in rats at exposure levels ~2.7 times the human exposure based on AUC at the 300-mg dose Advise pregnant women of the potential risk to a fetus Lactation There are no data on the presence of avapritinib or its metabolites in human milk or the effects of avapritinib on the breastfed child or milk production Advise women not to breastfeed during treatment and for 2 weeks following the final dose

Substrate of CYP3A4 and CYP2C9 Strong and moderate CYP3A inhibitors Avoid coadministration; reduce dose if unable to avoid Strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations and adverse reactions Strong and moderate CYP3A inducers Avoid coadministration Strong or moderate CYP3A inducer decreases plasma concentrations and efficacy of avapritinib Contraindicated (1) thalidomide

>10% All grades Decreased hemoglobin (81%) Edema (72%) Increased bilirubin (69%) Nausea (64%) Decreased leukocytes (62%) Fatigue (61%) Increased AST (51%) Decreased phosphate (49%) Cognitive impairment (48%) Decreased neutrophils (43%) Vomiting (38%) Decreased appetite (38%) Diarrhea (37%) Decreased potassium (34%) Increased lacrimation (33%) Abdominal pain (31%) Decreased albumin (31%) Decreased magnesium (29%) Increased creatinine (29%) Decreased sodium (28%) Decreased platelets (27%) Increased INR (24%) Constipation (23%) Rash (23%) Dizziness (22%) Hair color changes (21%) Increased ALT (19%) Headache (17%) Dyspnea (17%) Sleep disorders (16%) Taste effects (15%) Pyrexia (14%) Increased alkaline phosphatase (14%) Mood disorders (13%) Alopecia (13%) Decreased weight (13%) Increased activated partial thromboplastin time (13%) Pleural effusion (12%) Grade >3 Decreased hemoglobin (28%) Decreased phosphate (13%) 1-10% All grades Hypertension (8%) Thyroid disorders (hyperthyroid, hypothyroid) (3%) Palmar-plantar erythrodysesthesia (1%) Grade>3 Fatigue (9%) Increased bilirubin (9%) Abdominal pain (6%) Decreased neutrophils (6%) Decreased potassium (6%) Decreased sodium (7%) Decreased leukocytes (5%) Diarrhea (4.9%) Cognitive impairment (4.9%) Decreased appetite (2.9%) Nausea (2.5%) Dyspnea (2.5%) Rash (2.1%) Vomiting (2%) Edema (2%) Pleural effusion (2%) Decreased albumin (2%) Constipation (1.5%) Increased AST (1.5%) Mood disorders (1%) Decreased weight (1%) Decreased magnesium (1%) Increased alkaline phosphatase (1%) <1% Grade >3 Increased INR (0.6%) Pyrexia (0.5%) Dizziness (0.5%) Headache (0.5%) Hair color changes (0.5%) Decreased platelets (0.5%) Increased ALT (0.5%)

Tyrosine kinase inhibitor binds to and inhibits specific mutant forms of PDGFRα and c-Kit, including the PDGFRα D842V mutant and various KIT exon 17 mutants This results in the inhibition of PDGFRa- and c-Kit-mediated signal transduction pathways and the inhibition of proliferation in tumor cells that express these PDGFRa and c-Kit mutants