eXalt3

eXalt3 was an open-label, randomised phase 3 trial at 120 centres in 21 countries that compared ensartinib with crizotinib in 290 patients with advanced, recurrent or metastatic ALK-positive non-small-cell lung cancer who had not received an ALK inhibitor. Patients were randomised 1:1 to ensartinib 225 mg once daily (143) or crizotinib 250 mg twice daily (147). The primary endpoint was progression-free survival by blinded independent review, assessed in the intent-to-treat population and in a prespecified modified population with central-laboratory-confirmed ALK-positive disease.

In the intent-to-treat population, median progression-free survival was 25.8 months with ensartinib against 12.7 months with crizotinib (hazard ratio 0.51, 95% CI 0.35 to 0.72); in the modified population it was not reached against 12.7 months (hazard ratio 0.45). Among patients with target brain metastases at baseline, the intracranial response rate was 63.6 percent (7 of 11) against 21.1 percent (4 of 19) (JAMA Oncology 2021). The US label reports the same medians with a hazard ratio of 0.56 (95% CI 0.40 to 0.79) from its own analysis, response rates of 74 percent against 67 percent, median duration of response not estimable against 27.3 months among 106 and 98 responders, and a final overall survival of 63.2 against 55.7 months (hazard ratio 0.88, 95% CI 0.63 to 1.23) that was not statistically significant.

The trial supported the December 2024 US first-line approval of ensartinib (Ensacove). It compared ensartinib with crizotinib, not with alectinib or lorlatinib; ALEX, ALTA-1L and CROWN set the first-line benchmarks for the other next-generation inhibitors. The registry still lists the study as active and no longer recruiting for long-term follow-up.