Dr Chiappori on the Role of Ensartinib for ALK+ NSCLC With CNS Metastases

"We know that patients with ALK translocated tumors have a propensity, maybe more so that the general lung cancer patient to develop brain metastasis."

Alberto Chiappori, MD, a senior member of oncology and medicine for the Thoracic Oncology Program at the Moffitt Cancer Center, discussed the inclusion of patients with central nervous system (CNS) metastases in the phase 3 eXALT3 trial (NCT02767804), which evaluated ensartinib (Ensacove) for the treatment of adult patients with ALK-positive, locally advanced or metastatic non–small cell lung cancer (NSCLC).

The eXALT3 trial enrolled 290 patients who were randomly assigned 1:1 to receive either ensartinib or crizotinib (Xalkori). The primary end point was progression-free survival (PFS) assessed by blinded independent central review; overall survival (OS) was a key secondary end point.

The trial demonstrated a significant improvement in PFS with ensartinib vs crizotinib (HR, 0.56; 95% CI, 0.40-0.79; P = .0007) with a median PFS of 25.8 months (95% CI, 21.8-not estimable) in the ensartinib arm vs 12.7 months (95% CI, 9.2-16.6) in the crizotinib arm. These data supported the December 2024 FDA approval of ensartinib for the treatment of adult patients with ALK-positive, locally advanced or metastatic NSCLC who have not previously received an ALK inhibitor.

Chiappori emphasized the clinical importance of including patients with baseline brain metastases, noting that ALK-positive NSCLC exhibits a strong predilection for CNS involvement. Unlike earlier ALK inhibitors such as crizotinib, newer-generation agents like ensartinib have been designed to achieve improved CNS penetration and activity, making CNS efficacy a critical differentiating factor in the therapeutic landscape.

Because CNS progression is a common challenge in the management of ALK-positive NSCLC, Chiappori underscored the value of designing studies that reflect this real-world disease characteristic. Including patients with brain metastases in the eXALT3 trial enabled investigators to capture a more comprehensive assessment of ensartinib’s efficacy, particularly its activity against intracranial disease. The results provide evidence supporting the use of ensartinib as a first-line ALK-targeted therapy, including in patients with CNS disease at diagnosis.