Patients receiving adjuvant therapy with the second-generation ALK inhibitor ensartinib had longer disease-free survival than those receiving placebo following complete resection of ALK-positive non–small cell lung cancer, according to results of the phase 3 ELEVATE trial published in The New England Journal of Medicine. Overall survival data remained immature at the prespecified interim analysis.
The multicenter, double-blind, randomized trial enrolled adult patients with centrally confirmed ALK-positive stage IB to IIIB non–small cell lung cancer (NSCLC) who underwent complete surgical resection. Eligible patients had an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients with stage IIB to IIIB disease were required to have received adjuvant chemotherapy unless they declined chemotherapy or experienced unacceptable side effects. For those with stage IB or IIA disease, use of adjuvant chemotherapy was determined by the treating physician. The study did not permit preoperative or postoperative radiotherapy.
Participants were assigned in a 1:1 ratio to receive oral ensartinib 225 mg once daily or placebo following surgery and completion of any planned adjuvant chemotherapy. Treatment continued for as long as 24 months unless disease recurrence, unacceptable toxicity, or withdrawal of consent occurred sooner. Randomization was stratified according to disease stage and previous receipt of adjuvant chemotherapy. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIB disease. Disease-free survival in the overall stage IB to IIIB population served as the key secondary end point. Overall survival and safety were secondary end points, and central nervous system (CNS) disease–free survival was evaluated as an exploratory outcome.
From July 2022 through July 2024, investigators randomly assigned 274 patients, with 137 allocated to each study group. Baseline characteristics were reported as generally well balanced between the arms. Prior to randomization, adjuvant platinum-based chemotherapy had been administered to 89% of patients with stage IIB to IIIB disease and 24% of those with stage IB or IIA disease.
Among the 205 patients with stage II to IIIB disease, disease recurrence or death occurred in 12 assigned to ensartinib and 46 assigned to placebo. After a median follow-up of 24 months for disease-free survival, an estimated 86% of patients treated with ensartinib remained alive and disease-free at 24 months compared with 54% of those who received placebo.
In the overall population, disease recurrence or death occurred in 12 patients receiving ensartinib and 48 receiving placebo. At 24 months, the estimated proportion of patients who remained alive and disease-free was 87% with ensartinib and 57% with placebo.
“The disease-free survival benefit with ensartinib appeared to be consistent across nearly all prespecified subgroups, but the trial was not powered to assess significant differences in subgroups,” wrote lead author Dongsheng Yue, MD, of the Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China, and colleagues.
Disease recurrence occurred in 9% of patients treated with ensartinib and 34% of those receiving placebo. In both groups, the brain was the most common site of recurrence. In the exploratory analysis, ensartinib was found to be associated with a lower risk of CNS disease recurrence or death. Overall survival data remained immature at the interim analysis.
The safety population included all 274 treated patients. Adverse events occurred in 99% of patients receiving ensartinib and 92% of those receiving placebo, with most events classified as grade 1 or 2. Grade 3 or higher adverse events were reported in 36% and 18% of patients, respectively. Rash was the most common grade 3 or higher adverse event associated with ensartinib. Serious adverse events occurred in 18% of patients treated with ensartinib and 10% of those receiving placebo. Dose interruptions, dose reductions, and treatment discontinuations because of adverse events were more common with ensartinib. Fatal adverse events occurred in both groups, but investigators did not consider any to be treatment-related.
The investigators noted that all enrolled patients were Chinese, which may limit generalizability to other populations. They also stated that follow-up was insufficient to determine the effect on overall survival and that too few events had occurred to support a meaningful evaluation of ensartinib in patients with stage IB disease. Specific safety analyses for patients with stage IB disease and formal assessments of economic burden were not yet available.
The trial was funded by Betta Pharmaceuticals. Hangzhou Astrocyte Technology provided the immunohistochemical assay used to confirm ALK status. Author disclosures and the study's data-sharing statement are available with the published article.
Source: The New England Journal of Medicine