As reported in JAMA Oncology by Leora Horn, MD, MSc, FRCPC, and colleagues, the phase III eXalt3 trial has shown significantly prolonged progression-free survival with ensartinib vs crizotinib in patients with advanced, recurrent, or metastatic anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC) with no prior ALK inhibitor treatment.

Leora Horn, MD, MSc, FRCPC

Study Details

In the open-label trial, 290 patients with ALK-positive disease (intent-to-treat population) from sites in 21 countries were randomly assigned between July 2016 and November 2018 to receive ensartinib at 225 mg once daily (n = 143) or crizotinib at 250 mg twice daily (n = 147) until disease progression or unacceptable toxicity. Enrollment of patients with asymptomatic brain metastases was permitted. Patients may have received up to one prior chemotherapy regimen for metastatic disease. A modified intent-to-treat population consisted of 121 patients treated with ensartinib and 126 patients treated with crizotinib with central laboratory–confirmed ALK-positive disease. The primary endpoint was progression-free survival on blinded independent review committee assessment.

Progression-Free Survival

Median follow-up was 23.8 months (range = 0–44 months) in the ensartinib group and 20.2 months (range = 0–38 months) in the crizotinib group. In the intent-to-treat population, median progression-free survival was 25.8 months (95% confidence interval [CI] = 21.8 months–not reached) in the ensartinib group vs 12.7 months (95% CI = 9.2–16.6 months) in the crizotinib group (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.35–0.72, P < .001). In the modified intent-to-treat population, median progression-free survival was not reached (95% CI = 20.2 months–not reached) in the ensartinib group vs 12.7 months (95% CI = 8.9–16.6 months) in the crizotinib group (HR = 0.45, 95% CI = 0.30–0.66, P < .001).

Among patients with measurable brain metastases in the modified intent-to-treat population, intracranial response was observed in 7 (63.6%) of 11 ensartinib patients vs 4 (21.1%) of 19 crizotinib patients. Median progression-free survival among patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib (HR = 0.46, 95% CI = 0.27–0.77, P = .003), reflecting a reduced rate of central nervous system disease progression in the ensartinib group (4.2% vs 23.9% at 12 months; cause-specific HR = 0.32, 95% CI = 0.16–0.63, P = .001).

In the modified intent-to-treat population, at time of analysis, death had occurred in 30 patients (24.8%) in the ensartinib group vs 32 patients (25.4%) in the crizotinib group (HR = 0.91, 95% CI = 0.54–1.54); 2-year overall survival rates were 78% (95% CI = 69%–84%) vs 78% (95% CI = 70%–85%).

Adverse Events

In the intent-to-treat population, the most common ensartinib-related adverse events of any grade (primarily grade 1 or 2) were rash (67.8%), elevated alanine aminotransferase (48.3%) and aspartate aminotransferase (37.8%), and pruritus (26.6%). The most common ensartinib-related grade 3 adverse event was rash (11.2%); three grade 4 treatment-related adverse events were reported, consisting of increased bilirubin, increased creatine phosphokinase, and hyponatremia. Treatment-related serious adverse events occurred in 7.7% of patients in the ensartinib group vs 6.1% of the crizotinib group. Treatment-related adverse events led to discontinuation in 9.1% vs 6.8% of patients. No treatment-related deaths occurred in either group.

The investigators concluded, “In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC.”

Leora Horn, MD, MS, of Vanderbilt-Ingram Cancer Center, and Yi-Long Wu, MD, of Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, are the corresponding authors for the JAMA Oncology article.

Disclosure: The study was funded by Xcovery Holdings Inc. For full disclosures of the study authors, visit jamanetwork.com.