Ensartinib hydrochloride, an inhibitor of multiple receptor tyrosine kinases including anaplastic kinase (ALK), is an antineoplastic agent.1
Ensartinib is used for the treatment of locally advanced or metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in adults who have not previously received an ALK-inhibitor.1 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.1
The safety and efficacy of ensartinib, a second-generation ALK tyrosine kinase inhibitor (TKI), were established in a phase 3, open-label, multicenter, randomized study (eXalt3) in TKI-naïve adults with locally advanced or metastatic, ALK-positive NSCLC.1, 2, 3
In the eXALT3 study, 290 patients with advanced/recurrent or metastatic, ALK-positive NSCLC who were ALK TKI-naïve were randomized (stratified by prior chemotherapy, Eastern Cooperative Oncology Group [ECOG] performance status, CNS metastases at baseline, and geographic region) in a 1:1 ratio to receive either ensartinib (225 mg orally once daily) or crizotinib (250 mg orally twice daily) in 28-day cycles until disease progression or unacceptable toxicity.1, 3 An ensartinib dosage of 225 mg once daily was shown in a previous phase 1/2 study to be associated with high systemic and CNS response rates in ALK inhibitor-naïve patients.2, 3 In the eXALT2 study, ALK mutation status was initially determined via local testing; however, a protocol amendment required ALK testing to also be performed at a central laboratory using the FDA-approved Vysis fluorescence in situ hybridization (FISH) assay.3 Patients with asymptomatic brain metastases (not leptomeningeal disease) were eligible for enrollment, as well as patients who had received ≤1 prior chemotherapy regimen for metastatic disease.1, 3 Patients were not required to have progressive disease while receiving prior chemotherapy.3 Patients were excluded if they received cancer therapy within 4 weeks or radiotherapy within 14 days of study entry or if they received prior therapy with an ALK TKI, programmed death 1 (PD-1) inhibitor, or programmed death ligand 1 (PD-L1) inhibitor.1, 3 The primary outcome was progression-free survival (PFS) in the intention-to-treat (ITT) population as assessed by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).1, 3 Key secondary outcomes included overall survival (OS) (evaluated in the ITT population), and CNS response rate and CNS time to progression (both evaluated in the modified intention-to-treat [mITT] population).1, 3 The ITT population was comprised of 143 patients randomized to receive ensartinib and 147 patients randomized to receive crizotinib who tested positive for ALK through local testing prior to the protocol amendment.1, 3 Baseline demographics in the ITT population were similar between the treatment groups, though there were imbalances noted between Asian and non-Asian patients, with Asian patients being younger and having more brain metastases (40.8%) compared to non-Asian patients (30.1%).3 The median age of patients enrolled in eXALT3 was 54 years; 51% of patients were male, 56% were Asian, and 62% were never smokers.1, 3 The majority of patients (92%) had metastatic disease, and approximately 36% of patients had brain metastases at baseline.1, 3 Approximately 26% of patients received prior chemotherapy.1, 3 The mITT population was comprised of 247 patients randomized after the protocol amendment that required ALK-positive status to be confirmed via central laboratory testing, with 121 patients in the ensartinib group and 126 patients in the crizotinib group.3 The baseline demographics of the mITT population were similar to those of the ITT population and were balanced between treatment arms.3
During a pre-planned interim analysis, median PFS was prolonged in ensartinib-treated patients compared to crizotinib-treated patients (25.8 versus 12.7 months).1, 3 Median follow-up was 23.8 months in the ensartinib group and 20.2 months in the crizotinib group.3 Overall response rate was 74% in the ensartinib group and 67% in the crizotinib group, and complete response was achieved in 12 and 5% of the respective treatment groups.1 The median duration of response was not estimable in ensartinib-treated patients and was 27.3 months in crizotinib-treated patients.1, 3 At the time of the interim PFS analysis, OS results were immature.1, 3 However, at the time of final analysis, there was no significant difference in OS between ensartinib- (63.2 months) and crizotinib-treated patients (55.7 months).1 In patients without brain metastases at baseline, a lower percentage of ensartinib-treated patients developed brain metastases at 12 months compared to crizotinib-treated patients (4.2 versus 23.9%).3 In this population, median PFS was not reached in ensartinib-treated patients, with 61% disease-free at 36 months compared to 25% of crizotinib-treated patients.3 In patients with brain metastases at baseline, the median PFS was 11.8 months for ensartinib-treated patients and 7.5 months for crizotinib-treated patients.3 The CNS overall response rate was increased in ensartinib- compared to crizotinib-treated patients (59 versus 21%).1, 3 In the ensartinib and crizotinib groups, 44.7% and 61.4% of PFS events, respectively, involved the CNS.3
Approximately 60% of patients with lung cancer have driver alterations (e.g., in the epidermal growth factor receptor and ALK and BRAF genes).35 A relatively small subset of patients with NSCLC (approximately 3-7%) have ALK-positive disease, which indicates potential responsiveness to ALK inhibitor therapy (e.g., alectinib, brigatinib, ceritinib, crizotinib, ensartinib).1, 48, 50, 51, 52 Patients with this form of lung cancer typically are nonsmokers or have a history of light smoking, are female, and are younger in age and often have adenocarcinoma histology.50, 51, 52, 53 Although crizotinib is highly active in patients with ALK-positive NSCLC, most patients treated with the drug eventually experience disease progression, limiting the drug's long-term therapeutic potential.48, 50, 53 Disease progression in patients receiving crizotinib can result from acquired resistance mutations in ALK, amplification of gene expression, activation of alternate signaling pathways, and/or progression of brain metastases (because of poor distribution of crizotinib into the CSF).48, 49, 50, 51, 53
The American Society of Clinical Oncology (ASCO) Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alternations Living Guideline addresses treatment recommendations for patients with ALK-positive disease.8 For patients with an ALK rearrangement, a performance status (PS) of 0-2, and previously untreated NSCLC, alectinib, brigatinib, or lorlatinib should be offered in the first-line setting.8 If alectinib, brigatinib, or lorlatinib are not available, ceritinib or crizotinib should be offered.8 In the second-line setting, alectinib, brigatinib, or ceritinib should be offered if crizotinib was given in the first-line setting.8 Lorlatinib should be offered if alectinib or brigatinib were given in the first-line setting.8 In the third-line setting, lorlatinib should be offered if crizotinib was given in the first-line setting, followed by either alectinib, brigatinib, or ceritinib in the second-line setting.8 Ensartinib is not mentioned in this guideline as the drug was approved after the guideline was published.1
Of note, the eXALT3 trial spanned a major shift in recommended first-line therapy options for metastatic ALK-positive NSCLC.1, 4, 5, 6, 7, 8, 35 When the eXALT3 trial began in 2016, 3 ALK TKIs were FDA-approved for use in this setting: crizotinib (first-generation) and ceritinib and alectinib (second-generation).1, 3, 4, 9, 10, 13 At that time, crizotinib was the recommended agent for ALK-positive NSCLC in the first-line setting.5, 6, 7 Two additional ALK TKIs (brigatinib [second-generation] and lorlatinib [third-generation]) subsequently received FDA approval in 2017 and 2018, respectively.10, 11 The appropriateness of continuation of the eXALT3 study with a crizotinib comparator arm was evaluated; ultimately, the FDA agreed that crizotinib was an acceptable comparator for assessing the efficacy of ensartinib as a first-line therapy, and the eXALT3 study was continued.4 In early 2021, ASCO and Ontario Health (OH; formerly known as Cancer Care Ontario) published a joint guideline recommending the second-generation ALK TKIs (alectinib and brigatinib) as the preferred options over crizotinib in the first-line setting.35 The eXALT3 trial formally concluded in 2024 and ensartinib received FDA approval in December 2024.1, 3, 4 With the change in recommended first-line therapy options occurring during the eXALT3 trial, additional studies are needed to determine ensartinib's place of therapy in the treatment of ALK-positive NSCLC.1, 3, 8
Administer ensartinib orally once daily, at the same time each day, with or without food.1
The capsules should be swallowed whole and should not be crushed, chewed, or opened; the contents should not be dissolved.1
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.1
If vomiting occurs after administration of ensartinib, do not take an additional dose, and take the next dose at its scheduled time.1
Store capsules at 20-25°C (excursions permitted to 15-30°C).1 Store in the original container with dessicant to protect from moisture.1
Dosage of ensartinib hydrochloride is expressed in terms of ensartinib.1
The recommended adult dosage of ensartinib for the treatment of locally advanced or metastatic ALK-positive NSCLC in patients who have not previously received an ALK-inhibitor is 225 mg orally once daily, with or without food.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse events occur during therapy, temporary interruption, dosage reduction, and/or discontinuance of ensartinib may be necessary.1 If dosage reduction is necessary, an initial reduction to 200 mg once daily is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 150 mg once daily.1 Once the dosage has been reduced for adverse reactions, do not subsequently increase the dose of ensartinib.1 If a dosage of 150 mg is not tolerated, ensartinib should be permanently discontinued.1
Interstitial Lung Disease (ILD)/Pneumonitis
If any grade of ILD/pneumonitis occurs, permanently discontinue therapy.1, 14
If grade 3 or 4 elevation (>5 times the upper limit of normal [ULN]) of either ALT or AST occurs with concurrent total bilirubin elevation ≤2 times ULN, withhold ensartinib until recovery to grade ≤1 (i.e., ≤3 times ULN) or to baseline.1, 14 Resume at a reduced dosage.1
If grade 2-4 elevation (>3 times ULN) of either ALT or AST occurs with concurrent total bilirubin elevation >2 times ULN in the absence of cholestasis or hemolysis, permanently discontinue therapy.1, 14
Dermatologic Adverse Reactions
If grade 1 dermatologic adverse reactions occur, consider topical corticosteroids.1, 14
If grade 2 dermatologic adverse reactions occur, administer topical corticosteroids.1, 14 If no improvement in ≤7 days after initiation of topical steroids, administer oral corticosteroids.1 If no improvement in ≤7 days after initiation of oral corticosteroids, withhold ensartinib until recovery to grade ≤1.1 Resume at a reduced dosage.1
If grade 3 dermatologic adverse reactions occur, withhold ensartinib.1, 14 Administer topical corticosteroids.1 If no improvement after 7 days of initiation of topical steroids, administer oral corticosteroids.1 Once symptoms are improved to grade ≤1, resume ensartinib at a reduced dosage.1
If grade 4 dermatologic adverse reactions occur, permanently discontinue ensartinib.1, 14 Administer systemic corticosteroids and consider antibiotic use.1
If symptomatic, but non-life-threatening, bradycardia occurs, withhold ensartinib until recovery to asymptomatic bradycardia or to a resting heart rate of ≥60 beats per minute (bpm).1 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.1 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.1
If bradycardia with life-threatening consequences and urgent intervention indicated occurs, permanently discontinue ensartinib if no contributing concomitant medication is identified.1 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.1 For recurrence, permanently discontinue ensartinib.1
If grade 3 hyperglycemia (i.e., glucose >250 mg/dL) occurs despite optimal antihyperglycemic therapy, or if grade 4 hyperglycemia occurs, withhold ensartinib until hyperglycemia is adequately controlled.1, 14 Resume at a reduced dosage.1 If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ensartinib.1
If grade 2-3 visual disturbances occur, withhold ensartinib until recovery to grade 1 or baseline, then consider resuming at a reduced dosage.1, 14
If grade 4 visual disturbances occur, permanently discontinue ensartinib.1, 14
Increased Creatine Phosphokinase
If CPK elevation >5 times ULN occurs, withhold ensartinib until recovery to ≤2.5 times ULN or baseline, then resume at the same dosage.1
If CPK elevation >10 times ULN or second occurrence of CPK elevation >5 times ULN occurs, withhold ensartinib until recovery to ≤2.5 times ULN or baseline, then resume at a reduced dosage.1
If symptomatic or grade 4 hyperuricemia occurs, initiate urate-lowering medication.1, 14 Withhold ensartinib until improvement of signs or symptoms.1 Resume at same or reduced dosage.1
If grade 3-4 adverse reactions occur, withhold ensartinib until recovery to grade 1 or baseline.1, 14 Resume at a reduced dosage.1
If recurrent grade 4 adverse reactions occur, permanently discontinue ensartinib.1, 14
No dosage modification is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1-1.5 times ULN and any AST).1
Monitor patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3 ULN and any AST) for adverse reactions and subsequent need for dosage reduction.1
Avoid use of ensartinib in patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST), as safety and efficacy have not been studied in this population.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
Interstitial Lung Disease/Pneumonitis
Ensartinib may cause severe interstitial lung disease (ILD)/pneumonitis.1 In a pooled safety analysis, ILD/pneumonitis occurred in 5% of ensartinib-treated patients, including grade 3 events in 1.3% of patients and grade 4 in 0.4% of patients.1 Dose interruption occurred in 0.4% of patients, and permanent discontinuation was necessary in 1.5% of patients.1
If ILD/pneumonitis are suspected, immediately withhold ensartinib.1 If ILD/pneumonitis is confirmed, permanently discontinue ensartinib.1
Ensartinib may cause hepatic toxicity, including drug-induced liver injury.1 In a pooled safety analysis, ALT and AST elevations occurred in 59% and 58% of ensartinib-treated patients, with grade 3 ALT and AST elevations occurring in 5% and 1.8% of patients, respectively.1 The median time to first onset of elevated ALT or AST was 5.3 weeks.1 Dose interruption due to increased ALT and/or AST occurred in 4.6% of patients, dose reduction occurred in 2.6% of patients, and permanent discontinuation was necessary in 1.1% of patients.1
Increased bilirubin occurred in 12% of patients, including grade 3 events in 2.3% of patients and grade 4 in 0.2% of patients.1 One case of drug-induced liver injury occurred.1 Dose interruption due to increased bilirubin occurred in 1.3% of patients, dose reduction occurred in 0.7% of patients, and permanent discontinuation was necessary in 1.3% of patients.1
Monitor liver function tests at baseline and every 2 weeks during the first cycle of treatment with ensartinib, and then monthly and as clinically indicated.1 Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of the hepatic toxicity.1
Dermatologic Adverse Reactions
Ensartinib may cause dermatologic adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), rash, pruritus, and photosensitivity.1 In a pooled safety analysis, dermatologic adverse reactions occurred in 80% of patients, including grade 3 events in 14% of patients.1 Rash was the most commonly reported dermatologic adverse reaction, occurring in 72% of patients, including grade 3 in 12% of patients.1 The median time to onset of rash was 9 days.1 Pruritus was reported in 32% of patients, with grade 3 pruritus occurring in 2.4%.1 Photosensitivity occurred in 0.9% of patients, all of which were grade 1.1 One grade 3 case of DRESS was reported.1 Dose interruption occurred in 2.1% of patients, dose reduction occurred in 11% of patients, and permanent discontinuation was necessary in 1.5% of patients.1
Monitor patients for signs and symptoms of dermatologic adverse reactions.1 Patients should limit direct sun exposure while taking ensartinib and for at least 1 week after discontinuation.1 If dermatologic adverse reactions occur, treatment with antihistamines and topical or systemic steroids should be considered, based on the severity of the reaction.1 Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of the dermatologic adverse reaction.1
Ensartinib may cause symptomatic bradycardia.1 In a pooled safety analysis, bradycardia (HR <60 bpm) occurred in 6% of patients, all of which were grade 1 or 2 events.1 Dose interruption occurred in 0.4% of patients, and dose reduction occurred in 0.2%.1
Monitor heart rate regularly.1 Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of the bradycardia.1
Ensartinib can cause hyperglycemia.1 In a pooled safety analysis, elevated blood glucose occurred in 44% of patients, including grade 3 events in 2.5%.1 The median time to onset of increased blood glucose was 5.9 weeks.1
Monitor fasting serum glucose at baseline and regularly during treatment with ensartinib.1 Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of the hyperglycemia.1
Ensartinib may cause visual disturbances, including blurred vision, diplopia, photopsia, vitreous floaters, visual impairment, visual field defect, and reduced visual acuity.1 In a pooled safety analysis, 8% of ensartinib-treated patients experienced a visual disturbance, including grade 3 events in 0.2%.1 Visual disturbances led to dose interruption in 0.4% of patients.1
Monitor patients for new or worsening visual symptoms during treatment with ensartinib.1 If visual disturbances occur, an ophthalmic evaluation should be obtained.1 Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of the visual disturbance.1
Increased Creatine Phosphokinase (CPK)
Increased CPK has been reported with ensartinib treatment.1 In a pooled safety analysis, 43% of patients experienced elevated CPK values, including grade 3 and 4 elevations occurring in 1.5% and 0.5% of patients, respectively.1 The median time to onset of elevated CPK was 123 days.1 Dose interruption occurred in 0.2% of patients, and dose reduction occurred in 0.4%.1
Monitor patients for new or worsening muscle pain, tenderness, or weakness, and regularly monitor CPK levels during treatment with ensartinib.1 Temporary interruption followed by dosage reduction or permanent discontinuation may be necessary depending on the severity of the CPK elevation.1
Ensartinib can cause hyperuricemia.1 In a pooled safety analysis, 6% of patients experienced hyperuricemia, including grade 3 and grade 4 events occurring in 0.4% and 0.7% of patients, respectively.1 Of these patients, 11 required intervention, including hydration in 9 (1.9%) and urate-lowering medication in 2 (0.4%). 1
Monitor serum uric acid levels at baseline and periodically during treatment with ensartinib.1 Initiate treatment with urate-lowering therapy as clinically indicated.1 Temporary interruption followed by dosage reduction may be necessary depending on the severity of the hyperuricemia.1
Fetal/Neonatal Morbidity and Mortality
Based on findings from animal studies and its mechanism of action, ensartinib can cause fetal harm.1 There are no adequate and well-controlled studies in humans.1 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.1 For females of reproductive potential, pregnancy status should be verified prior to initiation of therapy with ensartinib.1 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.1
FD&C Yellow No. 5 (Tartrazine)
Ensartinib contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in susceptible patients.1 Overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity is low in the general population; however, it is frequently seen in patients who also have aspirin hypersensitivity.1
There are no available human data on ensartinib use in pregnant women.1 However, based on animal studies, ensartinib can cause fetal harm when administered during pregnancy.1 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.1
Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1
Verify the pregnancy status of females of reproductive potential prior to initiating ensartinib.1
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.1
It is not known whether ensartinib is distributed into human milk.1 Effects of the drug on breastfed infants or milk production are also not known.1 However, 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.1
Females and Males of Reproductive Potential
Based on animal studies, ensartinib can cause embryo-fetal harm when administered to a pregnant woman.1 Verify pregnancy status prior to initiating treatment with ensartinib.1
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.1
Safety and efficacy of ensartinib have not been established in pediatric patients <18 years of age.1
In clinical studies, 16% of 458 patients were ≥65 years of age.1 Exploratory analysis suggests that geriatric patients (≥65 years of age) experience a 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.1
Ensartinib is primarily metabolized by the liver.1 Patients with hepatic impairment may have increased exposure.1 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.1 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.1 Avoid use in patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST); safety and efficacy not established in this population.1
Mild or moderate renal impairment does not appear to have a clinically important effect on the pharmacokinetics of ensartinib; however, the effects of severe or end-stage renal disease on the pharmacokinetics of the drug have not been studied.1
The most common adverse reactions (incidence ≥20%) reported with ensartinib in clinical studies were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia.1
Ensartinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1
In vitro studies indicate that ensartinib is a substrate of P-glycoprotein (P-gp), but is not a substrate of breast cancer resistance protein (BCRP), organic anion protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, or OCT 2.1
In vitro studies indicate that ensartinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and does not induce CYP1A2, CYP2B6, or CYP3A.1
In vitro studies indicate that ensartinib also does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, or OCT3.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Moderate to Strong CYP3A4 Inhibitors
Ensartinib is primarily metabolized by CYP3A4.1 In vitro data suggest that concomitant use of ensartinib with moderate to strong CYP3A4 inhibitors may lead to increased ensartinib exposure.1 Avoid use of moderate to strong CYP3A4 inhibitors during ensartinib treatment.1
Moderate to Strong CYP3A4 Inducers
Ensartinib is primarily metabolized by CYP3A4.1 In vitro data suggest that concomitant use of ensartinib with moderate to strong CYP3A4 inducers may lead to decreased ensartinib exposure.1 Avoid use of moderate to strong CYP3A4 inducers during ensartinib treatment.1
Drugs Affecting or Affected by Transport Systems
Ensartinib is a substrate of P-gp.1 In vitro data suggest that concomitant use of ensartinib with P-gp inhibitors may lead to increased ensartinib exposure.1 Avoid use of P-gp inhibitors with ensartinib.1
Drugs Associated with Bradycardia
Ensartinib has been associated with bradycardia.1 If clinically important bradycardia occurs with concomitant use of ensartinib and other drugs known to cause bradycardia (including hypotensive agents), the dosage of the concomitant drug should be adjusted or the concomitant drug should be discontinued, if possible.1
Ensartinib hydrochloride, an inhibitor of multiple tyrosine kinases, including ALK, mesenchymal-epithelial transition factor (MET), and c-ros oncogene-1 (ROS1), is an antineoplastic agent.1 In vitro, the drug 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 S6.1
Activating mutations or translocations of the ALK gene have been identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK).2, 3, 50, 51, 52, 53 Such ALK gene rearrangements have been identified in approximately 3-11% of patients with non-small cell lung cancer (NSCLC).2, 3, 50, 51, 52, 53 Formation of ALK fusion proteins such as EML4-ALK results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.51, 52, 53
Although the ALK inhibitor crizotinib has demonstrated improved outcomes in patients with NSCLC harboring ALK mutations, secondary resistance to crizotinib eventually develops, generally within the first 1-2 years of treatment.2, 3, 51, 52, 53, 19 Clinical resistance to crizotinib has been attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways.2, 3, 50, 51, 53, 19 More potent ALK inhibitors (e.g., alectinib, ceritinib) were developed to overcome resistance to crizotinib; however, resistance to these drugs also develops over time.2, 3, 9, 10, 19 Secondary mutations of ALK are responsible for about 30% of cases of acquired crizotinib resistance and gene amplification is implicated in 9% of these cases.2, 3, 20, 52, 53, 19 The CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF; development and/or progression of brain metastases occurs in approximately one-half of patients during crizotinib treatment.2, 3, 20, 50, 51, 53, 19 In models, ensartinib demonstrated dose-dependent antitumor activity against tumor cells expressing EML4-ALK, including several cell lines with demonstrated resistance to crizotinib (e.g., L1196M, C1156Y, F1174, S1206R, T1151, and to a lesser extent, G1202R).2, 4
Following oral administration, peak plasma concentrations of ensartinib are achieved at a median of 3 hours.1 Administration of ensartinib with a high-fat meal did not produce clinically significant differences in pharmacokinetics compared to fasted conditions.1 Ensartinib is 91.6% bound to human plasma protein.1 Ensartinib is primarily metabolized by CYP3A4.1 Following oral administration of a single 200 mg dose of radiolabeled ensartinib, 91% of the dose is eliminated in the feces (38% as unchanged drug) and 10% in the urine (4.4% as unchanged drug).1 The mean plasma half-life of ensartinib is 30 hours.1 Age (20-86 years), sex, race (Asian versus White), body weight (38-148 kg), mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-89 mL/minute), and mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to 1.5 times ULN and any AST) do not have clinically important effects on the pharmacokinetics of ensartinib.1
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.
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.21 Contact manufacturer or consult the manufacturer's website ([Web]) for information regarding availability and purchasing.21
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 25 mg (of ensartinib) | Ensacove™ | Xcovery Holdings |
100 mg (of ensartinib) | Ensacove™ | Xcovery Holdings |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Xcovery Holdings, Inc. ENSACOVE™ (ensartinib) capsules prescribing information. Miami, FL; 2024 December.
2. Horn L, Infante JR, Reckamp KL, et al. Ensartinib (X-396) in ALK-positive non-small cell lung cancer: Results from a first-in-human phase I/II, multicenter study. Clin Cancer Res. 2018;24(12):2771-2779.
3. Horn L, Wang Z, Wu G, et al. Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer: A randomized clinical trial. JAMA Oncol. 2021;7(11):1617-1625.
4. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 218171Orig1s000: Integrated review. 2024 Dec 18. From FDA website.
5. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385-2394.
6. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167-2177.
7. Blackhall F, Cappuzzo F. Crizotinib: from discovery to accelerated development to front-line treatment. Ann Oncol. 2016;27 Suppl 3:iii35-III41.
8. Singh N, Temin S, Baker S Jr, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO living guideline. J Clin Oncol. 2022;40(28):3310-3322.
9. Novartis Pharmaceuticals Corporation. ZYKADIA® (ceritinib) capsules prescribing information. East Hanover, NJ; 2021 October.
10. Genentech, Inc. ALECENSA® (alectinib) capsules prescribing information. South San Francisoco, CA; 2024 April.
11. Takeda Pharmaceuticals America, Inc. ALUNBRIG® (brigatinib) tablets prescribing information. Lexington, MA; 2022 February.
12. Pfizer, Inc. LORBRENA® (lorlatinib) tablets prescribing information. New York, NY; 2021 March.
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