Ensartinib (Monograph)

Brand name: Ensacove
Drug class: Antineoplastic Agents

Introduction

Antineoplastic agent; an inhibitor of several tyrosine kinases, including anaplastic lymphoma kinase (ALK).

Uses for Ensartinib

Non-small Cell Lung Cancer

Management of locally advanced or metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in adult patients who have not previously received an ALK-inhibitor. Select patients for treatment with ensartinib based on the presence of ALK rearrangement in tumor specimens; an FDA-approved companion diagnostic for selecting patients for treatment with ensartinib is not currently available.

Clinical practice guidelines recommend second- and third-generation ALK tyrosine kinase inhibitors (TKIs) (alectinib, brigatinib, lorlatinib) as first-line agents for patients with ALK-positive NSCLC. Second- and third-generation ALK TKIs (alectinib, brigatinib, lorlatinib) are also recommended in the second- and third-line settings. Ensartinib, a second-generation ALK TKI, is not mentioned in these guidelines as the drug was approved after the guidelines were published.

Ensartinib Dosage and Administration

General

Pretreatment Screening

Select patients for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with ensartinib based on presence of anaplastic lymphoma kinase (ALK) rearrangement in tumor specimens. An FDA-approved companion diagnostic to detect ALK rearrangements for selecting patients for treatment with ensartinib is not currently available.
Evaluate liver function tests (e.g., ALT, AST, and total bilirubin).
Evaluate fasting blood glucose.
Evaluate serum uric acid levels.
Verify pregnancy status of females of reproductive potential.

Patient Monitoring

Monitor for new or worsening symptoms indicative of interstitial lung disease (ILD) or pneumonitis (e.g., dyspnea, cough, and/or fever).
Monitor liver function tests (e.g., ALT, AST, and total bilirubin) every 2 weeks during the first cycle of treatment, then once monthly and as clinically indicated.
Monitor for dermatologic adverse reactions (e.g., drug reaction with eosinophilia and systemic symptoms (DRESS), rash, pruritus, and photosensitivity).
Monitor heart rate regularly during treatment.
Monitor serum glucose periodically during treatment.
Monitor for new or worsening visual symptoms (e.g., blurred vision, diplopia, photopsia, vitreous floaters, visual impairment, visual field defect, and reduced visual acuity) and obtain ophthalmologic evaluation if visual disturbances occur.
Monitor CPK levels during treatment, and for any new or worsening muscle pain, tenderness, or weakness.
Monitor serum uric acid levels periodically during treatment.

Administration

Administer orally once daily at the same time each day without regard to meals.

Swallow capsules whole; do not crush, chew, open, or dissolve contents.

If a dose of ensartinib is missed, take the missed dose as soon as it is remembered, unless the next dose is due within 12 hours.

If vomiting occurs after administration of ensartinib, do not take an additional dose, and take the next dose at its scheduled time.

Dosage

Dosage of ensartinib hydrochloride is expressed in terms of ensartinib.

Adults

Non-small Cell Lung Cancer

Oral

225 mg once daily.

Dosage Modification for Toxicity

Modify dosage for adverse events as described in Table 1. When an initial dosage reduction is required, reduce dosage to 200 mg once daily. If further dosage reduction is necessary, the dosage should be reduced to 150 mg once daily. Once dosage has been reduced for adverse reactions, do not subsequently increase the dose. If a dosage of 150 mg is not tolerated, permanently discontinue ensartinib.

Oral

Table 1. Dosage Modification for Toxicity in Patients with NSCLC Receiving Ensartinib114
Adverse Reaction	Severity Grade	Ensartinib Dosage Modification
Interstitial Lung Disease/Pneumonitis	Any grade	Permanently discontinue
Hepatotoxicity	Grade 3–4 elevation (>5 times ULN) of ALT or AST with concurrent total bilirubin elevation ≤2 times ULN	Withold ensartinib until recovery to grade ≤1 (i.e., ≤3 times ULN) or baseline Resume at reduced dosage
	Grade 2–4 elevation (>3 times ULN) of either ALT or AST with concurrent total bilirubin elevation >2 times ULN in the absence of cholestasis or hemolysis	Permanently discontinue
Dermatologic Adverse Reactions	Grade 1	Consider topical corticosteroids
	Grade 2	Administer topical corticosteroids If no improvement in ≤7 days after initiation of topical steroids, administer oral corticosteroids If no improvement in ≤7 days after initiation of oral corticosteroids, withhold ensartinib until recovery to grade ≤1 Resume at a reduced dosage
	Grade 3	Withhold ensartinib; administer topical corticosteroids If no improvement after 7 days of initiation of topical steroids, administer oral corticosteroids Once symptoms are improved to grade ≤1, resume at a reduced dosage
	Grade 4	Permanently discontinue Administer systemic corticosteroids; consider antibiotic use
Bradycardia	Symptomatic, but non-life-threatening	Withhold ensartinib until recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 bpm If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume ensartinib at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of ≥60 bpm If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ensartinib at a reduced dosage upon recovery to asymptomatic bradycardia or to resting heart rate of ≥60 bpm
	Life-threatening consequences and urgent intervention indicated	Permanently discontinue if no contributing concomitant medication identified If contributing concomitant medication is identified and discontinued or dose adjusted, resume ensartinib at a reduced dosage upon recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 bpm, with frequent monitoring as clinically indicated For recurrence, permanently discontinue ensartinib
Hyperglycemia	Grade 3 (i.e., glucose >250 mg/dL) despite optimal antihyperglycemic therapy OR Grade 4	Withhold ensartinib until hyperglycemia is adequately controlled Resume at a reduced dosage If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue
Visual Disturbances	Grade 2–3	Withhold ensartinib until recovery to grade 1 or baseline Consider resuming at a reduced dosage
	Grade 4	Permanently discontinue
Increased CPK	>5 times ULN	Withhold ensartinib until recovery to ≤2.5 times ULN or baseline Resume at the same dosage
	>10 times ULN or second occurrence of CPK elevation >5 times ULN	Withhold ensartinib until recovery to ≤2.5 times ULN or baseline Resume at a reduced dosage
Hyperuricemia	Symptomatic or Grade 4	Initiate urate-lowering medication Withhold ensartinib until improvement of signs or symptoms Resume at same or reduced dosage
Other Adverse Reaction	Grade 3–4	Withhold ensartinib until recovery to grade 1 or baseline Resume at a reduced dosage
	Recurrent Grade 4	Permanently discontinue

Special Populations

Hepatic Impairment

Mild (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1–1.5 times ULN and any AST): Dosage adjustment not necessary.

Moderate (total bilirubin >1.5 to ≤3 ULN and any AST): Monitor for adverse events and subsequent need for dosage reduction.

Severe (total bilirubin >3 times ULN and any AST): Avoid use.

Renal Impairment

Dosage adjustment not necessary.

Geriatric Patients

Dosage adjustment not necessary.

Cautions for Ensartinib

Contraindications

Hypersensitivity reaction to ensartinib hydrochloride, FD&C Yellow No. 5 (tartrazine), or to any of its components.

Warnings/Precautions

Interstitial Lung Disease/Pneumonitis

May cause severe interstitial lung disease (ILD)/pneumonitis.

If ILD/pneumonitis are suspected, immediately withhold ensartinib. If ILD/pneumonitis is confirmed, permanently discontinue ensartinib.

Hepatic Toxicity

May cause hepatic toxicity, including drug-induced liver injury. Median time to first onset of elevated ALT or AST was 5.3 weeks.

Monitor liver function tests at baseline and every 2 weeks during the first cycle of treatment, then monthly and as clinically indicated. Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on severity of the hepatic toxicity.

Dermatologic Adverse Reactions

May cause dermatologic adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), rash, pruritus, and photosensitivity.

Monitor patients for signs and symptoms of dermatologic adverse reactions. Patients should limit direct sun exposure while taking ensartinib and for at least 1 week after discontinuation. If dermatologic adverse reactions occur, treatment with antihistamines and topical or systemic steroids should be considered, based on severity of the reaction. Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of dermatologic adverse reaction.

Bradycardia

May cause symptomatic bradycardia.

Monitor heart rate regularly. Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on severity of the bradycardia.

Hyperglycemia

May cause hyperglycemia. Median time to onset of increased blood glucose was 5.9 weeks.

Monitor fasting serum glucose at baseline and regularly during treatment. Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of hyperglycemia.

Visual Disturbances

May cause visual disturbances, including blurred vision, diplopia, photopsia, vitreous floaters, visual impairment, visual field defect, and reduced visual acuity.

Monitor patients for new or worsening visual symptoms during treatment. If visual disturbances occur, ophthalmic evaluation should be obtained. Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of visual disturbance.

Increased Creatine Phosphokinase

Increased CPK reported. Median time to onset of elevated CPK was 123 days.

Monitor patients for new or worsening muscle pain, tenderness, or weakness, and regularly monitor CPK levels during treatment. Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on severity of the CPK elevation.

Hyperuricemia

May cause hyperuricemia.

Monitor serum uric acid levels at baseline and periodically during treatment. Initiate treatment with urate-lowering therapy as clinically indicated. Temporary interruption followed by dosage reduction may be necessary depending on the severity of hyperuricemia.

Fetal/Neonatal Morbidity and Mortality

Based on findings from animal studies and its mechanism of action, ensartinib can cause fetal harm. No adequate and well-controlled studies in humans. When administered to pregnant rats, embryo-fetal mortality, alterations to growth, and structural abnormalities occurred at maternal exposure approximately equivalent to the human exposure at the recommended dose of 225 mg per day.

For females of reproductive potential, pregnancy status should be verified prior to initiation of therapy with ensartinib.

Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment with ensartinib and for 1 week after the last dose.

FD&C Yellow No. 5 (Tartrazine)

Contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in susceptible patients. Overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity is low in the general population; however, frequently seen in patients who also have aspirin hypersensitivity.

Specific Populations

Pregnancy

No available human data on use in pregnant women. Based on animal studies, can cause fetal harm when administered to a pregnant woman. When administered to pregnant rats, embryo-fetal mortality, alterations to growth, and structural abnormalities occurred at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg per day.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify pregnancy status of females of reproductive potential prior to initiating ensartinib.

Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment with ensartinib and for 1 week after the last dose.

Lactation

Not known whether ensartinib is distributed into human milk. Effects of the drug on breastfed infants or milk production are also not known. Because of the potential for adverse effects in breastfed children, advise women not to breastfeed during treatment with ensartinib and for 1 week after the last dose.

Females and Males of Reproductive Potential

Based on animal studies, can cause embryo-fetal harm when administered to a pregnant woman. Verify pregnancy status prior to initiating treatment with ensartinib.

Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment with ensartinib and for 1 week after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Exploratory analysis suggests that geriatric patients (≥65 years of age) experience higher incidence of serious adverse events (43% vs 27%), more frequent adverse events leading to treatment discontinuations (18% vs 10%), and dose modifications (34% vs 16%) when compared to patients <65 years of age.

Hepatic Impairment

Patients with hepatic impairment may have increased exposures. Mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to 1.5 times ULN and any AST) does not appear to have a clinically important effect on the pharmacokinetics of ensartinib. Monitor patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3 ULN and any AST) for increased adverse reactions; dosage adjustment may be required. Avoid use in patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST); safety and efficacy not established.

Renal Impairment

Mild or moderate renal impairment does not appear to have a clinically important effect on pharmacokinetics; however, effects of severe or end-stage renal disease on pharmacokinetics of ensartinib not studied.

Common Adverse Effects

Most common adverse reactions (incidence ≥20%): rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, pyrexia.

Drug Interactions

Substrate of CYP3A4 and P-gp.

Does not inhibit or induce CYP isoenzymes.

Does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, or OCT3.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Moderate to Strong CYP3A4 Inhibitors: Ensartinib is a CYP3A4 substrate. Concomitant administration of ensartinib with moderate to strong CYP3A4 inhibitors may lead to increased ensartinib exposure and should be avoided.

Moderate to Strong CYP3A4 Inducers: Ensartinib is a CYP3A4 substrate. Concomitant administration of ensartinib with moderate to strong CYP3A4 inhibitors may lead to decreased ensartinib exposure and should be avoided.

Drugs Affecting or Affected by Transport Systems

P-gp Inhibitors: Ensartinib is a P-gp substrate. Concomitant administration of ensartinib with P-gp inhibitors may lead to increased ensartinib exposure and should be avoided.

Drugs Associated with Bradycardia

Ensartinib is associated with bradycardia. If clinically important bradycardia occurs with concomitant use of ensartinib and other drugs known to cause bradycardia, dosage of the concomitant drug should be adjusted or the concomitant drug should be discontinued, if possible.

Ensartinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved at a median of 3 hours.

Food

High-fat meal does not substantially affect pharmacokinetics of ensartinib.

Distribution

Plasma Protein Binding

91.6%.

Elimination

Metabolism

Primarily metabolized by CYP3A4.

Elimination Route

Eliminated in feces (91%; 38% as unchanged drug) and urine (10%; 4.4% as unchanged drug).

Half-life

30 hours.

Stability

Storage

Oral

Capsules

Room temperature between 20–25°C (excursions permitted to 15–30°C); store in original container with dessicant.

Actions

Inhibits several tyrosine kinases, including ALK.
Inhibits ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins signal transducer and activator of transcription 3 (STAT3), protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and ribosomal protein S6.
Activating mutations or translocations of the ALK identified in several malignancies; can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).
ALK gene rearrangements identified in approximately 3–11% of patients with NSCLC.
Clinical resistance to crizotinib attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways. CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF.
Ensartinib demonstrates dose-dependent antitumor activity against tumor cells expressing EML4-ALK, including several cell lines with resistance to crizotinib (e.g., L1196M, C1156Y, F1174, S1206R, T1151, and to a lesser extent, G1202R).

Advice to Patients

Inform patients of the risk of severe interstitial lung disease (ILD)/pneumonitis during treatment with ensartinib. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms.
Inform patients of the potential risk of hepatoxicity during treatment with ensartinib and of the need to monitor for AST, ALT, and total bilirubin elevations during treatment. Advise patients to inform their healthcare provider of any new or worsening symptoms.
Inform patients of the potential risk of dermatologic adverse reactions, including rash, pruritus, and photosensitivity during treatment. If dermatologic reactions occur, advise patients to limit sun exposure while taking the drug and for at least 1 week after the final dose.
Advise patients of the risk of bradycardia during treatment with ensartinib and to report any symptoms of bradycardia. Advise patients to inform their healthcare provider about the use of any heart or blood pressure medications during treatment.
Inform patients of the risks of new or worsening hyperglycemia during treatment with ensartinib and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that antihyperglycemic medications may need to be adjusted during treatment.
Advise patients to inform their healthcare provider of any new or worsening vision symptoms during treatment.
Inform patients of the signs and symptoms of CPK elevation and the need for monitoring during treatment with ensartinib. Advise patients to inform their healthcare provider of any new or worsening symptoms.
Inform patients of the signs and symptoms of hyperuricemia. Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia during treatment.
Advise females of reproductive potential of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ensartinib and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ensartinib and for 1 week after the last dose.
Advise patients that this product contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type or asthma-type reactions in certain susceptible persons (e.g., patients who also have aspirin hypersensitivity). Advise patients to contact their healthcare provider and seek medical help right away if they develop symptoms of an allergic reaction to FD&C Yellow No. 5 (tartrazine).
Advise patients not to breastfeed during treatment with ensartinib and for 1 week after the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ensartinib is obtained from specialty pharmacy distributors. Contact manufacturer or consult the manufacturer's website ([Web]) for availability and purchasing information.