Adjuvant Ensartinib Improves DFS in Resected ALK-Positive NSCLC

Adjuvant ensartinib (Ensacove) significantly improved disease-free survival (DFS) vs placebo in patients with completely resected, ALK-positive stage IB to IIIB non–small cell lung cancer (NSCLC), according to results from the phase 3 ELEVATE trial (NCT05341583) published in The New England Journal of Medicine.

What was the efficacy of ensartinib in the ELEVATE trial?

Among patients with stage II to IIIB disease, the percentage of those who were alive and disease free at 24 months—the primary end point—was 86.4% with ensartinib vs 53.5% with placebo (HR for disease recurrence or death, 0.20; 95% CI, 0.11-0.38; P <.001). The median DFS was not calculable with ensartinib vs 24.8 months (95% CI, 22.2-not estimable) with placebo. In the overall intention-to-treat population, the 24-month DFS rate was 87.3% with ensartinib vs 57.2% with placebo (HR, 0.20; 95% CI, 0.10-0.37; P <.001).

Disease recurrence occurred in 12 patients (8.8%) in the ensartinib group vs 46 patients (33.6%) in the placebo group, and the brain was the most common site of recurrence (3.6% vs 12.4%, respectively). Ensartinib was associated with a reduced risk of central nervous system (CNS) disease recurrence or death (HR, 0.22; 95% CI, 0.08-0.60). A DFS benefit favoring ensartinib was observed across nearly all prespecified subgroups, although the trial was not powered for subgroup comparisons. Overall survival (OS) data remained immature, with 3 deaths reported in the overall population.

What did the safety data show?

Adverse events (AEs) of grade 3 or higher occurred in 49 patients (35.8%) in the ensartinib group vs 25 patients (18.2%) in the placebo group; any-grade AEs occurred in 98.5% vs 92.0%. The most common AE with ensartinib was rash (81.0%; grade 3 or higher, 14.6%), followed by increased alanine aminotransferase and aspartate aminotransferase (45.3% each). Treatment-related grade 3 or higher AEs occurred in 27.0% vs 6.6% of patients, and serious AEs in 18.2% vs 10.2%.

One fatal AE (cerebral hemorrhage) occurred in the ensartinib group along with 2 (a traffic accident and acute leukemia) in the placebo group, none of which were considered related to treatment. AEs led to treatment discontinuation in 2.2% of the ensartinib group.

“The safety profile of adjuvant ensartinib was consistent with that reported previously for ensartinib in advanced disease, and no new safety signals were identified,” senior study author Changli Wang, MD, professor in the Department of Lung Cancer at Tianjin Medical University Cancer Institute and Hospital, wrote in the publication with study coinvestigators. “Adjuvant ensartinib represents an effective new therapeutic strategy for patients with completely resected ALK-positive NSCLC.”

How was ELEVATE designed?

ELEVATE was a double-blind, randomized, placebo-controlled phase 3 trial. From July 2022 through July 2024, a total of 274 patients with completely resected ALK-positive stage IB to IIIB NSCLC who had received adjuvant chemotherapy were randomly assigned 1:1 to ensartinib at 225 mg once daily (n = 137) or placebo (n = 137) for 24 months. All enrolled patients were Chinese; 99.3% had nonsquamous histology and 83.9% had never smoked.

The primary end point of the study was DFS in patients with stage II to IIIB disease. The key secondary end point was DFS in the overall population; other secondary end points included CNS DFS, OS, and safety.

The authors noted several limitations, including that all enrolled patients were Chinese, which limits generalizability. Additionally, follow-up was insufficient to determine an effect on OS, and the number of events was too small to meaningfully evaluate ensartinib in patients with stage IB disease.

The findings add to adjuvant ALK inhibitor data from the open-label phase 3 ALINA trial (NCT03456076), which evaluated alectinib (Alecensa), and parallel the adjuvant EGFR-directed phase 3 ADAURA trial (NCT02511106) of osimertinib (Tagrisso) that the authors cited as a precedent for a large DFS benefit potentially translating into an OS benefit. The authors also highlighted the ongoing neoadjuvant phase 2 NEOLORA trial (NCT06682884) of lorlatinib as a future direction for ALK inhibition in resectable NSCLC.

Reference

Yue D, Huang M, Song P, et al. Ensartinib in resected ALK-positive non–small-cell lung cancer. N Engl J Med. 2026;395(2):151-161. doi:10.1056/NEJMoa2518990