Pharmacist's Application to Practice: Ensartinib

FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer

What is the potential role for ensartinib in the treatment of non-small cell lung cancer?

• Ensartinib is a small molecule kinase inhibitor of anaplastic lymphoma kinase (ALK) indicated for the treatment of adult patients with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not previously received an ALK-inhibitor.1,2
• ALK gene rearrangement has been identified in 5–6% of NSCLC cases. There has been an increase in the prognosis for patients with ALK-positive NSCLC in recent years due to the development of ALK tyrosine kinase inhibitors.3
• Ensartinib drug approval was based on eXALT3 (NCT02767804), an open-label, multicenter, randomized, phase 3 trial conducted in patients 18 years or older with advanced, recurrent, or metastatic ALK-positive NSCLC.4
• eXALT3 enrolled 290 patients without previous ALK-inhibitor treatment who were randomized 1:1 to receive either ensartinib 225 mg once daily (n=143) or crizotinib 250 mg twice daily (n=147).
• The primary outcome was progression-free survival (PFS). The median PFS was significantly longer in the ensartinib group (25.8 months) than with the crizotinib group (12.7 months). The secondary endpoint, overall survival, was not shown to be statistically significant at the time of this writing (HR 0.88 [95% CI: 0.63, 1.23], p=0.4570).
• Treatment-related adverse events leading to dose reductions occurred in 34 of 143 (23.8%) of patients in the ensartinib group vs. 29 of 146 (19.9%) of patients in the crizotinib group. Adverse events leading to drug discontinuations occurred in 13 of 143 (9.1%) of patients in the ensartinib group and 10 of 146 (6.8%) of patients in the crizotinib group.
• The National Comprehensive Cancer Network (NCCN) lists ensartinib as a preferred first-line option for patients with NSCLC with ALK rearrangement discovered prior to or during first-line systemic therapy. 5

What role can the pharmacist play in the management of patients on ensartinib?

• Pharmacists can play a crucial role in the management of patients prescribed ensartinib, including ensuring appropriate dosing and dose reductions, adverse events management, adherence, and accessibility.
• Dosage and Administration
  • The starting dose of ensartinib is 225 mg by mouth once daily, with or without food and is continued until medication intolerance or disease progression.2
  • Renal impairment:
    • eGFR ≥ 30 mL/min: There are no dosage adjustments provided in the manufacturer’s labeling; similar clinical effects were observed in patients with eGFR 30-89 mL/min in studies.
    • eGFR ≤ 30 mL/min: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
  • Hepatic impairment:
    • Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 × ULN and any AST): No dosage adjustment is necessary.
    • Moderate impairment (total bilirubin >1.5 to ≤3 × ULN and any AST): Monitor for increased risk of adverse reactions and adjust ensartinib dosage as clinically indicated.
    • Severe impairment (total bilirubin >3 × ULN and any AST) impairment: Avoid use.
  • The package labeling provides dosage recommendations for toxicity development and treatment modification depends on severity. Dosing recommendations are provided for patients who develop:
    • Lab abnormalities including elevated uric acid, creatinine phosphokinase, blood glucose, and liver function tests while on treatment.
    • Adverse effects involving vision changes, bradycardia, skin toxicity, or other grade 3 adverse effects. Pneumonitis or interstitial lung disease necessitate permanent discontinuation.
  • Refer to the package insert for additional information on holding, dose adjustment, and permanent discontinuation for toxicity.
  • Where a dose reduction is warranted, the first recommended dose reduction is to 200 mg orally once daily. The second recommended dose reduction is to 150 mg orally once daily. It is recommended to permanently discontinue ensartinib if the patient is unable to tolerate 150 mg orally once daily.
  • Ensartinib is available in two capsule sizes: 25 mg and 100 mg.
• Adverse Effects and Management:
  • The most common AEs (≥ 20%): rash, musculoskeletal pain, constipation, pruritis, cough, nausea, edema, vomiting, fatigue, and pyrexia.
  • The ensartinib package labeling provides guidance on dosing and management for select adverse reactions including interstitial lung disease/pneumonitis, hepatotoxicity, skin reactions, bradycardia (heart rate < 60 bpm), hyperglycemia, vision changes, increased CPK, hyperuricemia, and other grade 3-4 toxicities.
• Monitoring:
  • Prior to initiation: LFTs, fasting blood glucose, heart rate, verify pregnancy status in patients with reproductive potential.
    • Advise females of reproductive potential or males with partners of reproductive potential to utilize effective contraception during and 1 week after the last dose.
  • Periodically during treatment: LFTs, creatine phosphokinase, serum glucose, uric acid levels, and heart rate.
  • Ensartinib is a substrate of CYP3A4 (major) and P-glycoprotein (P-gp)/ABCB1 (major).
    • Avoid concomitant use of moderate/strong CYP3A4/5 inducers and inhibitors.
    • Avoid concomitant use of P-gp inhibitors.

Clinical Pearls

• Capsules must be swallowed whole and cannot be crushed or chewed. Capsules should not be opened or the contents of the capsule dissolved.
• If a dose is missed, then the missed dose should be taken as soon as possible unless the next dose is due within 12 hours. Two doses should not be taken on the same day.
• If vomiting occurs after a dose is taken, an additional dose should not be taken and the next dose should be taken at its schedule time.
• Ensartinib contains FD&C Yellow No. 5 (tartrazine). Therefore, patients with an allergy to tartrazine should not receive ensartinib.
• Ensartinib can be stored at controlled room temperature 20ºC to 25ºC (68ºF to 77ºF). Store and dispense in the original bottle with desiccant to protect from moisture. Do not remove desiccant from bottle. Keep out of reach of children.2
• At the time of this writing, no patient assistance programs have been listed by the drug manufacturer’s website.

References

1.FDA approves ensartinib for Alk-positive locally advanced or metastatic non-small cell lung cancer. U.S. Food and Drug Administration. Published December 18, 2024. Accessed February 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ensartinib-alk-positive-locally-advanced-or-metastatic-non-small-cell-lung-cancer.

2.ENSACOVE (ensartinib) [prescribing Information]. Miami, FL: Xcovery Holdings; December 2024.

3.Du X, Shao Y, Qin HF, Tai YH, Gao HJ. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer. 2018;9(4):423-430.

4.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.

5.National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 3.2025). https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed February 17, 2025.