ENSACOVE Capsule Ref.[115492] Active ingredients: Ensartinib

Exposure-response relationship

Ensartinib exposure-response relationships and the time course of the pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

At the approved recommended dosage, a mean increase in the QTc interval >20 ms was not observed.

Ensartinib mean (coefficient of variation [CV%]) maximum concentration (C_max) is 292 ng/mL (60%), and the area under the concentration-time curve (AUC_0–24h) is 4,920 ng·h/ml (62%) at the approved recommended dosage. Ensartinib steady state is reached within 15 days with a mean accumulation ratio of 2.7.

Absorption

Ensartinib median (minimum, maximum) time to reach C_max (T_max) at steady state is 3 hours (2, 8 hours).

Effect of Food

No clinically significant differences in ensartinib pharmacokinetics were observed following administration of ENSACOVE with a high-fat meal (total 800-1000 calories, >50% fat) compared to fasted conditions.

Distribution

Ensartinib mean (CV%) apparent volume of distribution is 1,720 L (42%). Ensartinib is 91.6% bound to human plasma protein.

Elimination

Ensartinib mean (standard deviation [SD]) steady-state half-life (t_1/2) is 30 (20) hours.

Metabolism

Ensartinib is predominantly metabolized by CYP3A.

Excretion

Following a single oral 200 mg dose of radiolabeled ensartinib, 91% of the radioactivity was recovered in feces (38% as unchanged) and 10% in urine (4.4% as unchanged).

Specific Populations

No clinically significant differences in the pharmacokinetics of ensartinib were observed based on age (20 to 86 years), sex, race (Asian vs White), body weight (38 to 148 kg), mild to moderate renal impairment (eGFR 30 to 89 mL/min) and mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin 1 to 1.5 x ULN and any AST).

The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR <15 mL/min) with or without hemodialysis, and moderate (total bilirubin >1.5 to ≤3 ULN and any AST) or severe (total bilirubin >3 times ULN and any AST) hepatic impairment on ensartinib pharmacokinetics is unknown.

Drug Interaction Studies

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Ensartinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and does not induce CYP1A2, CYP2B6, or CYP3A.

Transporter Systems: Ensartinib is a P-gp substrate but is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2.

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

Carcinogenicity studies have not been conducted with ensartinib.

Ensartinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human lymphocyte chromosome aberration assay or an in vivo rat bone marrow micronucleus assay.

Dedicated fertility studies were not conducted with ensartinib. No adverse effects on male or female reproductive organs were observed in up to 3-month repeat-dose toxicology studies conducted in rats and dogs.

14.1 TKI-naive ALK-Positive Locally Advanced or Metastatic NSCLC (eXALT3 Study)

The efficacy of ENSACOVE was evaluated in the eXALT3 study (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 and an ECOG performance status of 0, 1, or 2. Patients could have received one prior regimen of chemotherapy but could not have previously received an ALK-targeted therapy.

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. Randomization was stratified by prior chemotherapy (0 vs. 1), ECOG performance status (0 or 1 vs. 2), presence of central nervous system (CNS) metastases (yes or no), and geographic region (Asia vs. the rest of the world). 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). The baseline demographic characteristics of the overall study population were median age 54 years (range: 25-90); 16% age >65 years; 51% male; 56% Asian; 41% White and 1.4% Black; 8% Hispanic or Latino; ECOG PS 0 or 1 (95%); and 62% never smokers. Patients had Stage IIIB (8%) or Stage IV NSCLC (92%); 26% had received prior chemotherapy for advanced disease and 17% had received prior radiation. 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:

CI = Confidence Interval, NE=not estimable, BICR = Blinded Independent Central Review
^a p-value based on unstratified log-rank test

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 0.88 (95% CI: 0.63, 1.23).

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):

BICR = Blinded Independent Central Review; CI = Confidence Interval