Ensacove Drug Information

Generic name: ENSARTINIB

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Uses of Ensacove

ENSACOVE is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC)as detected by an FDA-approved test who have not previously received an ALK-inhibitor.

Dosage & Administration of Ensacove

Patient Selection

Select patients for the treatment of locally advanced or metastatic NSCLC with ENSACOVE based on the presence of ALK rearrangement(s) in tumor specimens. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostics.

Recommended Testing and Advice Prior to Initiating ENSACOVE Prior to initiating ENSACOVE, evaluate liver function tests and fasting blood glucose.

Recommended Dosage

The recommended dosage of ENSACOVE is 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Swallow capsules whole, do not crush or chew. Do not open or dissolve the contents of the capsule.

Take ENSACOVE at the same time each day. Missed dose If a dose is missed, then take the missed dose as soon as possible unless the next dose is due within 12 hours. Do not take 2 doses on the same day.

Vomiting If vomiting occurs after taking a dose, do not take an additional dose and take the next dose at its scheduled time.

Dosage Modification for Adverse Reactions

The recommended dose reductions for adverse reactions are provided in Table 1. Table 1: Recommended Once the dose has been reduced for adverse reactions, do not subsequently increase the dose of ENSACOVE. The recommended dosage modifications for the management of adverse reactions are provided in Table 2.

Table 2: Recommended ENSACOVE Dosage Modifications for Adverse Reactions Adverse Reaction Severity* ENSACOVE Dose Modification and Management for Adverse Reactions Interstitial Lung Disease (ILD)/Pneumonitis

Table 1: Recommended Dose Reductions for Adverse Reactions
Dose Reduction	Recommended Dose and Schedule
First	200 mg orally once daily
Second	150 mg orally once daily
Permanently discontinue ENSACOVE if patients are unable to tolerate 150 mg orally once daily.

Table 2: Recommended ENSACOVE Dosage Modifications for Adverse Reactions
Adverse Reaction	Severity*	ENSACOVE Dose Modification and Management for Adverse Reactions
Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions ( 5.1 )]	Any Grade	Permanently discontinue ENSACOVE.
Hepatotoxicity [see Warnings and Precautions ( 5.2 )]	Grade 3 or 4 elevation (greater than 5 times ULN) of either ALT or AST with concurrent total bilirubin less than or equal to 2 times ULN	Withhold ENSACOVE until recovery to Grade ≤1 (≤3 times ULN) or to baseline. Resume ENSACOVE at reduced dose as per Table 1.
Hepatotoxicity [see Warnings and Precautions ( 5.2 )]	Grade 2 to 4 elevation (greater than 3 times ULN) of either ALT or AST with concurrent total bilirubin elevation greater than 2 times ULN in the absence of cholestasis or hemolysis	Permanently discontinue ENSACOVE.
Dermatologic Adverse Reactions [see Warnings and Precautions ( 5.3 )]	Grade 1	Consider topical corticosteroids.
	Grade 2	Administer topical corticosteroids. If not improved in ≤7 days after initiation of topical corticosteroids, administer oral corticosteroids. If not improved in ≤7 days after initiation of oral corticosteroids, withhold ENSACOVE until recovery to Grade ≤1. Resume ENSACOVE at reduced dose as per Table 1.
	Grade 3	Withhold ENSACOVE. Administer topical corticosteroids. If not improved after 7 days of initiation of topical corticosteroids, administer oral corticosteroids. Resume ENSACOVE at reduced dose as per Table 1 upon improvement to Grade ≤1.
	Grade 4	Permanently discontinue ENSACOVE. Administer systemic corticosteroids and consider antibiotic use.
Bradycardia (HR less than 60 bpm) [see Warnings and Precautions ( 5.4 )]	Symptomatic bradycardia	Withhold ENSACOVE until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above. If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume ENSACOVE at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above. If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ENSACOVE at reduced dose as per Table 1 upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.
	Bradycardia with life-threatening consequences, urgent intervention indicated	Permanently discontinue ENSACOVE if no contributing concomitant medication is identified. If contributing concomitant medication is identified and discontinued or dose- adjusted, resume ENSACOVE at reduced dose as per Table 1 upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. For recurrence, permanently discontinue ENSACOVE.
Hyperglycemia [see Warnings and Precautions ( 5.5 )]	Grade 3 (greater than 250 mg/dL) despite optimal anti- hyperglycemic therapy OR Grade 4	Withhold ENSACOVE until hyperglycemia is adequately controlled, then resume ENSACOVE at reduced dose as per Table 1. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ENSACOVE.
Visual Disturbance [see Warnings and Precautions ( 5.6 )]	Grade 2 or 3	Withhold ENSACOVE until recovery to Grade 1 or baseline, then consider resuming at reduced dose as per Table 1.
	Grade 4	Permanently discontinue ENSACOVE.
Increased Creatine Phosphokinase [see Warnings and Precautions ( 5.7 )]	CPK elevation greater than 5 times ULN	Temporarily withhold ENSACOVE until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at same dose.
	CPK elevation greater than 10 times ULN or second occurrence of CPK elevation of greater than 5 times ULN	Temporarily withhold ENSACOVE until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at reduced dose as per Table 1.
Hyperuricemia [see Warnings and Precautions ( 5.8 )]	Symptomatic or Grade 4	Initiate urate-lowering medication. Withhold ENSACOVE until improvement of signs or symptoms. Resume ENSACOVE at same or reduced dose.
Other Adverse Reactions [see Adverse Reactions ( 6.1 )]	Grade 3 or 4	Withhold ENSACOVE until recovery to Grade 1 or baseline. Resume ENSACOVE at reduced dose as per Table 1.
Other Adverse Reactions [see Adverse Reactions ( 6.1 )]	Recurrent Grade 4	Permanently discontinue ENSACOVE.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; bpm = beats per minute; HR = heart rate; ULN = upper limit of normal *Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.03.

Side Effects of Ensacove

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ENSACOVE as a single agent in 458 patients with locally advanced or metastatic ALK-positive NSCLC in the following trials: eXALT3 Study N= 5 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. In this pooled safety population, the most common adverse reactions (≥20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia.

The most frequent Grade 3 or 4 laboratory abnormalities (≥2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase. TKI-naive ALK-Positive Locally Advanced or Metastatic NSCLC The safety of ENSACOVE was evaluated in the eXALT3 study. Patients received ENSACOVE 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity.

Among patients who received ENSACOVE, 78% were exposed for 6 months or longer and 66% were exposed for greater than one year. Serious adverse reactions occurred in 23% of patients treated with ENSACOVE. One fatal adverse reaction (0.7%) occurred due to bronchopneumonia.

Permanent discontinuation of ENSACOVE due to an adverse reaction occurred in 12% of patients. Dose interruptions of ENSACOVE due to an adverse reaction occurred in 41% of patients. Dose reductions of ENSACOVE due to an adverse reaction occurred in 24% of patients.

Tables 3 and 4 summarize the most frequent adverse reactions and laboratory abnormalities, respectively. Table 3: Adverse Reactions ( ≥10%) in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study Table 4: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study Clinically relevant adverse reactions in <10% of patients who received ENSACOVE included interstitial lung disease, photosensitivity, increased creatinine phosphokinase, bradycardia, and visual disturbances.

Table 3: Adverse Reactions ( ≥10%) in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study
	ENSACOVE N = 143		Crizotinib N = 146
Adverse Reaction	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Skin and Subcutaneous Tissue Disorders
Rash a	66	12	10	0
Pruritus b	30	2.1	4.1	0
Alopecia	11	0	4.8	0
Dry Skin	10	0.7	0.7	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Pain c	36	1.4	20	0
Respiratory, Thoracic and Mediastinal Disorders
Cough d	31	0.7	16	0
Gastrointestinal Disorders
Constipation	31	0	26	0
Nausea	28	1.4	30	2.1
Vomiting e	16	0.7	32	0
General Disorders and Administration Site Conditions
Edema f	27	2.1	28	2.1
Pyrexia g	22	0.7	10	0.7
Fatigue h	21	0.7	14	1.4
Metabolism and Nutrition Disorders
Decreased appetite	15	0	12	1.4
Infection and Infestation
Respiratory Tract Infection	13	0.7	10	0
Nervous System Disorders
Dizziness i	12	0.7	14	0.7
Dysgeusia	10	0	11	0
Vascular Disorders
Hemorrhage j	10	1.4	4.8	0
Adverse reactions were graded using NCI CTCAE version 4.03. a Includes dermatitis, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, exfoliative rash, palmar-plantar erythrodysaesthesia, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, skin exfoliation, and vulvovaginal rash b Includes ear pruritus, eye pruritus, eyelids pruritus, lip pruritus, pruritus, and pruritus generalized c Includes arthritis, spinal pain, myalgia, musculoskeletal pain, back pain, pain in extremity, neck pain, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort d Includes cough, productive cough, upper-airway cough syndrome e Includes vomiting and retching f Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, gravitational edema, skin edema, eye edema, and periorbital edema g Includes pyrexia and hyperthermia h Includes fatigue and asthenia i Includes dizziness, vertigo, postural dizziness j Includes hemoptysis, intracranial hemorrhage, gastrointestinal hemorrhage, hematuria, upper gastrointestinal hemorrhage, vaginal hemorrhage, gingival bleeding, vitreous hemorrhage, epistaxis, rectal hemorrhage, anal hemorrhage

Table 4: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study
	ENSACOVE N = 143		Crizotinib N = 146
Lab Abnormality	All Grades %	Grade 3 or 4 %	All Grades %	Grade 3 or 4 %
Chemistry
Alanine aminotransferase increased	73	5	74	8
Alkaline phosphatase increased	64	2.2	50	0.7
Aspartate aminotransferase increased	64	1.4	62	3.5
Glucose increased	49	5	35	0.7
Albumin decreased	46	0.7	56	1.4
Phosphate decreased	39	7	42	4.9
Urate increased	39	39	27	27
Creatinine increased	37	0	27	0
Calcium decreased	36	1.4	64	4.9
Sodium decreased	27	4.3	27	4.2
Hematology
Lymphocytes decreased	57	7	47	5
Hemoglobin decreased	43	0.7	31	1.4
Adverse reactions were graded using NCI CTCAE version 4.03. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase

Warnings & Cautions for Ensacove

Interstitial Lung Disease/Pneumonitis ENSACOVE can cause severe interstitial lung disease (ILD)/pneumonitis. ILD/pneumonitis leading to dose interruption occurred in 0.4% and permanent discontinuation of ENSACOVE in 1.5% of patients. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever) during treatment with ENSACOVE.

Immediately withhold ENSACOVE in patients with suspected ILD/pneumonitis. Permanently discontinue ENSACOVE if ILD/pneumonitis is confirmed.

Hepatotoxicity ENSACOVE can cause hepatotoxicity including drug-induced liver injury. In the pooled safety population, 59% of patients treated with ENSACOVE had increased alanine aminotransferase (ALT), including 5% Grade 3. Increased aspartate aminotransferase (AST) occurred in 58% of patients treated with ENSACOVE, including 1.8% Grade 3.

There was one case of drug-induced liver injury in ENSACOVE-treated patients. The median time to first onset of increased ALT or AST was 5.3 weeks (range: 0.4 to 152 weeks). The dose of ENSACOVE was interrupted in 4.6% of patients for increased ALT or AST.

Increased ALT or AST leading to dose reduction occurred in 2.6% and permanent discontinuation of ENSACOVE in 1.1% of patients. The dose of ENSACOVE was interrupted in 1.3% of patients for increased bilirubin. Increased bilirubin leading to dose reduction occurred in 0.7% and permanent discontinuation of ENSACOVE in 1.3% of patients.

Monitor liver function tests including ALT, AST, and total bilirubin at baseline and every 2 weeks during the first cycle of treatment with ENSACOVE, and then monthly and as clinically indicated. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on the severity of the adverse reaction.

Dermatologic Adverse Reactions ENSACOVE can cause dermatologic adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), rash, pruritus, and photosensitivity. In the pooled safety population, dermatologic adverse reactions occurred in 80% of patients receiving ENSACOVE, including Grade 3 in 14% of patients. Rash occurred in 72% of patients receiving ENSACOVE, including Grade 3 in 12% of patients.

The median time to onset of rash was 9 days (range: 1 day to 17.3 months). Pruritus occurred in 32% of patients receiving ENSACOVE, with Grade 3 in 2.4%. There was one Grade 3 case (0.2%) of drug reaction with eosinophilia and systemic symptoms (DRESS).

The dose of ENSACOVE was interrupted in 12% of patients for dermatologic adverse reactions. Dermatologic adverse reactions leading to dose reduction occurred in 11% and permanent discontinuation of ENSACOVE in 1.5% of patients. In the pooled safety population, photosensitivity occurred in 0.9% of patients receiving ENSACOVE; all were Grade 1.

Monitor patients for dermatologic adverse reactions during treatment with ENSACOVE. If dermatologic adverse reactions occur, treat with antihistamine, topical or systemic steroids based on the severity. Advise patients to limit direct sun exposure while taking ENSACOVE and for at least 1 week after discontinuation.

Bradycardia ENSACOVE can cause symptomatic bradycardia. In the pooled safety population, bradycardia (heart rate less than 60 beats per minute) occurred in 6% of patients treated with ENSACOVE. All bradycardia events were Grade 1 or 2.

Bradycardia requiring dose reduction occurred in 0.2% and led to dose interruption in 0.4% of ENSACOVE-treated patients. Monitor heart rate regularly during treatment with ENSACOVE.

Hyperglycemia ENSACOVE can cause hyperglycemia. In the pooled safety population, based on laboratory data, 44% of patients receiving ENSACOVE experienced increased blood glucose, including Grade 3 in 2.5%. The median time to onset of increased blood glucose was 5.9 weeks (0.4 weeks to 3.4 years).

Assess fasting serum glucose at baseline and monitor serum glucose periodically during treatment with ENSACOVE.

Visual Disturbances ENSACOVE can cause visual disturbances including blurred vision, diplopia, photopsia, vitreous floaters, visual impairment, visual field defect, and reduced visual acuity. In the pooled safety population, 8% of patients receiving ENSACOVE experienced visual disturbance, including 0.2% Grade 3. Visual disturbances led to dose interruption in 0.4% of patients.

Obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms during treatment with ENSACOVE.

Increased Creatine Phosphokinase In the pooled safety population, of the 203 patients with creatine phosphokinase (CPK) laboratory data available, increased CPK occurred in 43% of patients who received ENSACOVE. The median time to onset of increased CPK was 123 days (range: 13 days to 22 months). Increased CPK leading to dose interruption occurred in 0.2% and dose reduction in 0.4%.

Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during treatment with ENSACOVE.

Hyperuricemia ENSACOVE can cause hyperuricemia

Nine patients (1.9%) required hydration and two patients (0.4%) required urate-lowering medication. Monitor serum uric acid levels prior to initiating ENSACOVE and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated.

Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, ENSACOVE can cause fetal harm when administered to a pregnant woman. In embryo-fetal developmental studies, oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities. Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on area under the curve (AUC).

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ENSACOVE and for 1 week after the last dose.

FD&C Yellow No. 5 (Tartrazine) This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Drug Interactions with Ensacove

Effect of Other Drugs on ENSACOVE Table 5 describes drug interactions where concomitant use of another drug affects ENSACOVE. Table 5: Effect of Other Drugs on ENSACOVE Strong or Moderate CYP3A Inhibitors Prevention or Management Avoid concomitant use of strong or moderate CYP3A inhibitors with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro.

P-gp Inhibitors Prevention or Management Avoid concomitant use of P-gp inhibitors with ENSACOVE.

Table 5: Effect of Other Drugs on ENSACOVE
Strong or Moderate CYP3A Inhibitors
Prevention or Management	Avoid concomitant use of strong or moderate CYP3A inhibitors with ENSACOVE.
Mechanism and Clinical Effect(s)	This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro [see Clinical Pharmacology ( 12.3 )]. Concomitant use with strong or moderate CYP3A inhibitors may increase ensartinib exposure; however, this has not been studied clinically.
Strong or Moderate CYP3A Inducers
Prevention or Management	Avoid concomitant use of strong or moderate CYP3A inducers with ENSACOVE.
Mechanism and Clinical Effect(s)	This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro [see Clinical Pharmacology ( 12.3 )]. Concomitant use with strong or moderate CYP3A inducers may decrease ensartinib exposure; however, this has not been studied clinically.
P-gp Inhibitors
Prevention or Management	Avoid concomitant use of P-gp inhibitors with ENSACOVE.
Mechanism and Clinical Effect(s)	This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a P-gp substrate in vitro [see Clinical Pharmacology ( 12.3 )]. Concomitant use with P-gp inhibitors may increase ensartinib exposure; however, this has not been studied clinically.

Pregnancy Safety for Ensacove

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, ENSACOVE can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ENSACOVE in pregnant women to inform a drug-associated risk. Oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities.

Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC ( see Data ). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Ensartinib doses ≥40 mg/kg/day (approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC) resulted in an increase in the incidence of fetal malformations (aortic dislocation, ventricular septal defect, separated vertebrae) and dose-dependent delayed skeletal development, including decreased or delayed ossification of the vertebrae. Ensartinib at 80 mg/kg (approximately 6.4 times the human exposure at the recommended dose of 225 mg/day based on AUC) resulted in maternal toxicity (reduced body weight and food consumption), decreased fetal body weight, increased pre- and post-implantation loss, decreases in the number of live fetuses, and visceral variations (missing renal papillae, pyelectasis).

Pediatric Use of Ensacove

Pediatric Use The safety and effectiveness of ENSACOVE in pediatric patients have not been established.

Contraindications for Ensacove

ENSACOVE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ENSACOVE, FD&C Yellow No. 5 (tartrazine), or to any of its components.

Clinical Studies of Ensacove

TKI-naive ALK-Positive Locally Advanced or Metastatic

NSCLC (eXALT3 Study) The efficacy of ENSACOVE was evaluated in eXALT3 (NCT02767804), an open-label, randomized, active-controlled, multicenter study in adult patients with locally advanced (stage IIIB following prior chemotherapy or chemoradiation or not amenable to curative intent therapy) or metastatic ALK-positive NSCLC. Patients were required to have ALK-positive NSCLC in tumor specimens as determined in local laboratories using immunohistochemistry (IHC), next-generation sequencing (NGS), polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) tests. Of these patients, 85% (247/290) had centrally confirmed ALK rearrangements with the Vysis Break Apart FISH Probe Kit.

Patients could have received one prior regimen of chemotherapy but could not have previously received an ALK-targeted therapy; patients with an ECOG performance status of 0, 1, or 2 were eligible. Patients with asymptomatic, untreated brain metastases who were not on corticosteroids and patients with asymptomatic, treated brain metastases who were on stable or decreasing dose of corticosteroids were eligible. Patients were required to have completed radiation therapy at least 2 weeks, or chemotherapy at least 4 weeks, prior to enrollment.

Patients with leptomeningeal disease were ineligible. Patients were randomized 1:1 to receive ENSACOVE 225 mg orally once daily or crizotinib 250 mg orally twice daily in 28-day cycles until disease progression or unacceptable toxicity. Tumor assessments were performed every 8 weeks.

The main efficacy outcome measure was progression-free survival (PFS) as evaluated by Blinded Independent Central Review (BICR) according to RECIST version 1.1. The key secondary efficacy outcome measure was overall survival (OS); other secondary outcome measures included CNS response rate, time to CNS progression, and overall response rate (ORR). A total of 290 patients were randomized to ENSACOVE (n=143) or crizotinib (n=147).

Baseline CNS metastases were present in 36% of the patients. The eXALT3 study demonstrated a statistically significant improvement in PFS for patients randomized to ENSACOVE compared to patients randomized to crizotinib. The efficacy results as assessed by BICR are summarized in Table 6 and Figure 1.

Table 6: Efficacy Results for eXALT3 Study According to BICR Assessment Figure 1 Kaplan-Meier Plot of Progression-Free Survival by IRR from Study 301 (eXALT3) At the time of the primary PFS analysis, OS results were immature. At the time of final analysis of OS, there was no statistically significant difference (p-value = 0.4570) between ENSACOVE and crizotinib. Median OS was 63.2 months in the ENSACOVE arm and 55.7 months in the crizotinib arm, with the hazard ratio of The results of the pre-specified analyses of CNS response rate by BICR in patients with baseline measurable CNS disease are summarized in Table 7.

Table 7: IRR-assessed CNS Responses in Patients with Measurable CNS Disease at Baseline in Study 301 (eXALT3) Figure 1

Table 6: Efficacy Results for eXALT3 Study According to BICR Assessment
Efficacy Parameter	ENSACOVE N=143	Crizotinib N=147
Progression-free survival
Number of events, n (%)	59 (41%)	80 (54%)
Progressive disease, n (%)	51 (36%)	77 (52%)
Death, n (%)	8 (6%)	3 (2%)
Median, months (95% CI)	25.8 (21.8, NE)	12.7 (9.2, 16.6)
Hazard ratio (95% CI)	0.56 (0.40, 0.79)
p-value a	0.0008
Overall response rate
Overall response rate % (95% CI)	74% (66, 81)	67% (58, 74)
Complete response %	12%	5%
Partial response %	62%	61%
Duration of response
Number of responders, n	106	98
Median, months (95% CI)	NE (22.0, NE)	27.3 (12.9, NE)
CI = Confidence Interval, NE=not estimable, BICR = Blinded Independent Central Review a p-value based on unstratified log-rank test

Table 7: IRR-assessed CNS Responses in Patients with Measurable CNS Disease at Baseline in Study 301 (eXALT3)
Efficacy Parameter	ENSACOVE N=17	crizotinib N=24
CNS overall response rate % (95% CI)	59% (33, 82)	21% (7, 42)
Complete response %	24%	8%
Partial response %	35%	13%
Duration of Response
Number of responders, n	10	5
Patients with DOR ≥ 12 months	30%	40%
BICR = Blinded Independent Central Review; CI = Confidence Interval

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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