Brigatinib

Indications

Brigatinib is used for: Non-Small Cell Lung Cancer

Adult Dose

Non-Small Cell Lung Cancer Indicated for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients who have progressed on or are intolerant to crizotinib 90 mg PO qDay for the first 7 days; if 90 mg/day is tolerated, increase the dose to 180 mg PO qDay Continue until disease progression or unacceptable toxicity Hepatic impairment Mild or moderate (Child-Pugh A or B): No dose adjustment required Severe (Child-Pugh C): Reduce once daily dose by ~40% (eg, from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg)

Child Dose

Renal Dose

Renal impairment Mild or moderate (CrCl 30-89 mL/min): No dose adjustment required Severe (CrCl 15-29 mL/min): Reduce brigatinib dose by ~50% (eg, from 180 mg to 90 mg, or from 90 mg to 60 mg)

Administration

Take with or without food

Contra Indications

Precautions

Risk of interstitial lung disease (ILD)/pneumonitis; HTN; bradycardia; visual disturbances (eg, blurred vision, diplopia, & reduced visual acuity); creatine phosphokinase (CPK) & pancreatic enzyme elevation; hyperglycemia. Withhold treatment in patients w/ Grade 3 or 4 CPK elevation; Grade 3 or 4 pancreatic enzyme elevation; inadequate hyperglycemic control. Discontinue in case of Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis; Grade 4 HTN or recurrence of Grade 3 HTN; life-threatening bradycardia; Grade 4 visual disturbances. Use w/ caution in combination w/ antihypertensive agents causing bradycardia. Females of reproductive potential should use effective non-hormonal contraception during treatment & for at least 4 mth following the final dose. Males w/ female partners of reproductive potential should use effective contraception during treatment & for at least 3 mth after last dose. Pregnancy & lactation. Childn.

Pregnancy-Lactation

Pregnancy Based on its mechanism of action and findings in animals, can cause fetal harm when administered to pregnant women Administration to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (~0.7 times the human exposure by AUC at 180 mg once daily), as well as increased postimplantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (~1.26 times the human exposure at 180 mg once daily) or greater Infertility: Based on findings in male reproductive organs in animals, may cause reduced fertility in males Contraception Females: Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for at least 4 months after the final dose Counsel patients to use a nonhormonal method of contraception since brigatinib can render some hormonal contraceptives ineffective Males: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose Lactation Unknown if distributed in human breast milk Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment and for 1 week following the final dose

Interactions

Increased plasma conc & adverse reactions w/ strong CYP3A inhibitors [eg, certain antivirals (boceprevir, cobicistat, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), macrolide antibiotics (clarithromycin), antifungals (itraconazole, ketoconazole, posaconazole, voriconazole), conivaptan]; grapefruit or grapefruit juice. Decreased plasma conc & efficacy w/ strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin, St. John's Wort). Decreased conc & loss of efficacy of CYP3A substrates (eg, hormonal contraceptives).

Adverse Effects

Side effects of Brigatinib : >10% Increased AST (38%) Hyperglycemia (38%) Increased ALT (34%) Nausea (33%) Fatigue (29%) Headache (28%) Increased CPK (27%) Increased amylase (27%) Dyspnea (27%) Vomiting (24%) Anemia (23%) Decreased appetite (22%) Prolonged aPTT (22%) Increased lipase (21%) Diarrhea (19%) Constipation (19%) Lymphopenia (19%) Cough (18%) Abdominal pain (17%) Increased alkaline phosphatase (15%) Decreased phosphorous (15%) Rash (15%) Pyrexia (14%) Arthralgia (14%) Peripheral neuropathy (13%) Muscle spasms (12%) Hypertension (11%) Pain in extremity (11%) Insomnia (11%) 1-10% Back pain (10%) Myalgia (9.2%) Visual disturbances (7.3%) Pneumonia (4.6%) Interstitial lung disease/pneumonitis (3.7%) <1% Hypoxia (0.9%)

Mechanism of Action

Tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases, including ALK, ROS1, insulinlike growth factor-1 receptor (IGF-1R), and FLT-3, as well as EGFR deletion and point mutations Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays Exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib Also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line