The U.S. Food and Drug Administration (FDA) has granted approval to ensartinib (Ensacove, Xcovery Holdings, Inc.) for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not previously received an ALK inhibitor. This approval marks a significant advancement in the therapeutic landscape for this specific subset of lung cancer patients. The decision was announced on December 18, 2024, offering a new treatment option with improved progression-free survival (PFS).
Efficacy Demonstrated in eXALT3 Trial
The approval is based on data from the phase 3 eXALT3 trial (NCT02767804), an open-label, randomized, active-controlled, multicenter study involving 290 patients with locally advanced or metastatic ALK-positive NSCLC who had not previously received ALK-targeted therapy. Patients were randomized 1:1 to receive either ensartinib or crizotinib. The primary efficacy outcome was progression-free survival (PFS) as evaluated by blinded independent central review. A key secondary outcome was overall survival (OS).
Ensartinib demonstrated a statistically significant improvement in PFS compared to crizotinib, with a hazard ratio (HR) of 0.56 (95% CI: 0.40, 0.79; p-value 0.0007). The median PFS was 25.8 months (95% CI: 21.8, not estimable) in the ensartinib arm and 12.7 months (95% CI: 9.2, 16.6) in the crizotinib arm. However, there was no statistically significant difference in OS (HR 0.88 [95% CI: 0.63, 1.23], p-value 0.4570).
Leora Horn, MD, MS, and eXalt3 study co-authors noted, "Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC. In this randomized clinical trial, ensartinib showed superior systemic and intracranial efficacy compared with crizotinib and an overall favorable safety profile that is distinct from that of other agents in this class."
Safety and Adverse Reactions
The most common adverse reactions (≥20%) reported with ensartinib were rash, musculoskeletal pain, constipation, cough, pruritus, nausea, edema, pyrexia, and fatigue. Healthcare professionals are advised to monitor patients for these adverse events and manage them according to established guidelines.
Dosing and Administration
The recommended dose of ensartinib is 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. This oral administration provides a convenient option for patients.
Impact on Treatment Landscape
The introduction of ensartinib as a first-line option expands the therapeutic choices for patients with ALK-positive NSCLC. This approval offers a new treatment option, enabling health care providers to personalize treatment plans more effectively. Ensartinib joins a growing list of ALK inhibitors approved for NSCLC, including alectinib, brigatinib, and lorlatinib.
Ongoing Research
Future research should investigate primary and acquired resistance mechanisms to optimize the sequencing of ensartinib and other ALK inhibitors in the first-line setting. Studies are also underway to address skin toxicities seen with the combination therapy.
Giovanni Selvaggi, Chief Medical Officer of Xcovery, described ensartinib as a “novel and distinct first-line therapeutic option to ALK-positive NSCLC patients.”
