Clinical Pharmacology Corner: FDA Approves VIZIMPRO (Dacomitinib)

FDA Approves VIZIMPRO (Dacomitinib) for the First-line Treatment of Patients with Metastatic Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 19 Deletion or Exon 21 L858R Substitution Mutations as Detected by an FDA-Approved Test 

On September 27, 2018, the U.S. Food and Drug Administration (FDA) approved VIZIMPRO (dacomitinib) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. 

Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at:http://www.fda.gov/CompanionDiagnostics. The approved recommended dosage of VIZIMPRO is 45 mg orally once daily, until disease progression or unacceptable toxicity occurs. VIZIMPRO can be taken with or without food. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with VIZIMPRO and for at least 17 days after the final dose.

Severe and fatal interstitial lung disease (ILD)/pneumonitis occurred in patients treated with VIZIMPRO. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Withhold VIZIMPRO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Permanently discontinue VIZIMPRO if ILD is confirmed.

Severe and fatal diarrhea occurred in patients treated with VIZIMPRO. Withhold VIZIMPRO for Grade 2 or greater diarrhea until recovery to less than or equal to Grade 1 severity, then resume VIZIMPRO at the same or a reduced dose depending on the severity of diarrhea. Promptly initiate anti-diarrheal treatment (loperamide or diphenoxylate hydrochloride with atropine sulfate) for diarrhea.

Rash and exfoliative skin conditions reactions occurred in patients treated with VIZIMPRO. The incidence and severity of rash and exfoliative skin reactions is increased with sun exposure.

Recommendations for dose administration and dose modifications of VIZIMPRO for the management of adverse reactions are described in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) 

• MOA: Dacomitinib is an irreversible inhibitor of the kinase activity of the human epidermal growth factor receptor (EGFR) family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation).   
• General PK: Dacomitinib maximum plasma concentration (C_max) and area under the curve (AUC) at steady state increased proportionally over the dose range of VIZIMPRO 2 mg to 60 mg orally once daily (0.04 to 1.3 times the approved recommended dosage) in patients with cancer. At the approved recommended dose, the steady state the geometric mean C_max was 108 ng/mL (CV: 35%) and the AUC_0-24h was 2213 ng•h/mL (CV: 35%) in patients with solid tumors. Steady state was achieved within 14 days following repeated dosing and the estimated geometric mean accumulation ratio was 5.7 (CV: 28%) based on AUC.
• Absorption: Dacomitinib mean absolute bioavailability is 80% and the median T_max occurred at approximately 6 hours (range 2.0 to 24 hours) after a single oral dose of VIZIMPRO 45 mg in patients with cancer.
• Effect of Food: Administration of VIZIMPRO with a high-fat, high-calorie meal had no clinically meaningful effect on dacomitinib pharmacokinetics.
• Distribution: Dacomitinib geometric mean volume of distribution of was 1889 L (CV: 18%) and human plasma protein binding is approximately 98%, in vitro.  
• Elimination: Dacomitinib mean plasma half-life was 70 hours (CV: 21%) and the geometric mean apparent plasma clearance was 24.9 L/h (CV: 36%) following a single 45 mg oral dose of VIZIMPRO in patients with cancer.
• Metabolism: The main route of clearance of dacomitinib is hepatic metabolism. Dacomitinib is metabolized by cytochrome P450 (CYP) 2D6 to form the metabolite O-desmethyl dacomitinib, which had similar vitro pharmacologic activity as dacomitinib. The steady-state plasma trough concentration of O-desmethyl dacomitinib ranges from 7.4% to 19% of the parent. CYP3A4 also contributed to the formation of other minor oxidative metabolites.
• Excretion: Following oral administration of a single dose of 45 mg [¹⁴C] radiolabeled dacomitinib, 79% of the radioactivity was recovered in feces (20% as dacomitinib) and 3% in urine (< 1% as dacomitinib).
• PD: Higher exposures, across the range of exposures with the recommended dose of 45 mg daily, correlated with an increased probability of Grade ≥ 3 adverse events, specifically dermatological toxicities and diarrhea.

Drug Interactions

• Proton pump inhibitors (PPIs): Concomitant use with a PPI decreases dacomitinib concentrations, which may reduce VIZIMPRO efficacy. Avoid use with VIZIMPRO. As an alternative to PPI, use locally-acting antacids or H2-receptor antagonist. Administer VIZIMPRO at least 6 hours before or 10 hours after H2-receptor antagonist.  
• CYP2D6 substrates: Concomitant use of VIZIMPRO increases the concentration of drugs that are CYP2D6 substrates. Avoid concomitant use with VIZIMPRO where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities.

Use in Specific Populations

• Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). The pharmacokinetics of dacomitinib has not been adequately characterized in patients with severe renal impairment (CLcr < 30 mL/min) or studied in patients requiring hemodialysis and a recommended dose of VIZIMPRO has not been established in this population.  
• Hepatic Impairment: No dose adjustment is recommended in patients with mild (total bilirubin ≤ upper limit of normal [ULN] with AST > ULN or total bilirubin > 1 to 1.5 x ULN with any AST) or moderate (total bilirubin > 1.5 to 3 x ULN and any AST) hepatic impairment. The effect of severe hepatic impairment (total bilirubin between 3 to 10 x ULN and any AST) on dacomitinib pharmacokinetics is unknown and a recommended dose of VIZIMPRO has not been established in this population.

Efficacy and Safety

Efficacy of VIZIMPRO for the first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test was demonstrated in a randomized, multicenter, multinational, open-label study. The major efficacy outcome measure was progression-free survival (PFS) as determined by blinded Independent Radiology Central (IRC) review per RECIST v1.1. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.

The most common (≥ 1%) serious adverse reactions were diarrhea and IDL. The most common adverse reactions (≥ 20%) are diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, and pruritus.

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Full prescribing information is available at https://go.usa.gov/xPBTT.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.