Ensartinib

Based on findings from animal studies and its mechanism of action, ensartinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ensartinib 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. 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 2% to 4% and 15% to 20%, respectively.

There are no data on the presence of ensartinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with ensartinib and for 1 week after the last dose.

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.

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 ensartinib as a single agent in 458 patients with locally advanced or metastatic ALK-positive NSCLC in the following trials: eXALT3 Study (N=143), Study 101 (NCT01625234, N=98), Study BTP-28311 (NCT02959619, N=35), and

Study BTP-42322 (NCT03215693, N=182). Patients received ensartinib 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Among 458 patients who received ensartinib, 63% were exposed for 6 months or longer and 47% were exposed for greater than one year. 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 ensartinib was evaluated in the eXALT3 study. Patients received ensartinib 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Among patients who received ensartinib, 78% were exposed for 6 months or longer and 66% were exposed for greater than one year.

The median age of patients who received ensartinib was 54 years (range: 25-86); 50% male; 54% Asian, 43% White; 0.7% Black or African American; and 11% Hispanic or Latino.

Serious adverse reactions occurred in 23% of patients treated with ensartinib. Serious adverse reactions that occurred in ≥1% were pneumonia (4.9%), hemorrhage (2.1%), rash (2.1%) and cellulitis (1.4%). One fatal adverse reaction (0.7%) occurred due to bronchopneumonia.

Permanent discontinuation of ensartinib due to an adverse reaction occurred in 12% of patients. Adverse reactions which resulted in permanent discontinuation of ensartinib (≥1%) included increased ALT (2.1%), increased AST (2.1%), pneumonitis/ILD (2.1%). increased blood bilirubin (1.4%), and increased conjugated bilirubin (1.4%).

Dose interruptions of ensartinib due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dose interruptions (≥2%) included rash (13%), increased ALT (6%), pneumonia (3.5%), edema (2.8%), pruritus (2.8%), pyrexia (2.8%), increased AST (2.1%), hemorrhage (2.1%), and decreased appetite (2.1%).

Dose reductions of ensartinib due to an adverse reaction occurred in 24% of patients. Adverse reactions which required dose reductions (≥2%) included rash (11%), increased ALT (4.2%), pruritus (2.8%), and edema (2.1%).

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 Ensartinib in eXALT3 Study:

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 check 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 Ensartinib in eXALT3 Study:

Adverse reactions were graded using NCI CTCAE version 4.03.
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase

Clinically relevant adverse reactions in <10% of patients who received ensartinib included interstitial lung disease, photosensitivity, increased creatinine phosphokinase, bradycardia, and visual disturbances.