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Ensartinib Bests Crizotinib in ALK+ Non-Small Cell Lung Cancer

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Ensartinib significantly prolonged progression-free survival, compared with crizotinib, in patients with ALK-positive non-small-cell lung cancer (NSCLC) in the eXalt3 study.

Ensartinib, being developed by Xcovery Holdings, is a potent, next-generation, once-daily oral ALK inhibitor with broad preclinical activity against ALK-resistance mutations.

“Its potency is more than 10 times greater than that of crizotinib in enzyme assays,” Dr. Leora Horn of Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, said during an August 8 presentation at the International Association for the Study of Lung Cancer World Conference on Lung Cancer Virtual Presidential Symposium.

The eXalt3 trial is a global, phase-3, open-label trial involving patients with ALK+ NSCLC, an ECOG performance status of zero or two and no prior ALK-inhibitor treatment. Treatment consisted of 225 mg once-daily ensartinib or 250 mg twice-daily crizotinib.

The intention-to-treat (ITT) population included 290 patients with locally determined ALK+ NSCLC, with 143 in the ensartinib group and 147 in the crizotinib group. The modified ITT population (the prespecified patient population that was ALK+ as confirmed by central Abbott FISH test) included 247 patients, of whom 121 received ensartinib and 126 received crizotinib.

At the July 1, 2020 data cutoff, a total of 139 patients experienced disease progression, as assessed by a blinded independent review committee.

Median progression-free survival (PFS), the primary endpoint, was significantly longer with ensartinib than crizotinib (25.8 months vs. 12.7 months) in the ITT population (hazard ratio, 0.51; 95% confidence interval, 0.35 to 0.72), and was not reached with ensartinib versus 12.7 months with crizotinib in the modified ITT population (HR, 0.45; 95% CI, 0.3 to 0.66).

“With longer follow-up, ensartinib is trending toward further improved median PFS overall and in those without brain metastases at baseline,” Dr. Horn said.

In the modified ITT population, the overall response rate was 75% with ensartinib and 67% with crizotinib. Ensartinib also showed “superior efficacy in the brain over crizotinib,” Dr. Horn noted. The intracranial overall response rate among patients with measurable brain metastases was 64% with ensartinib versus 21% with crizotinib.

The median duration of response in the modified ITT population was not reached with ensartinib versus 27.3 months with crizotinib, and median overall survival was not reached in either treatment group (HR, 0.88; 95% CI, 0.52 to 1.5). Two-year overall rates were 78% in both groups.

“The study is strongly positive against an old comparator, which at the time was standard of care,” Dr. Giovanni Selvaggi, thoracic oncologist and Xcovery chief medical officer.

Being a second-generation ALK inhibitor, “you expect ensartinib to be better than crizotinib and it was much better than crizotinib in pretty much any single efficacy endpoint, notably in the primary endpoint agreed with the FDA (U.S. Food and Drug Administration), which is the median PFS in the intent-to-treat population as assessed by independent readers,” Dr. Selvaggi said.

Ensartinib showed a favorable safety profile with low-grade rash and transaminitis being the most common treatment-related adverse events. Serious grade-3 or -4 treatment-related adverse events occurred among 8% of patients in the ensartinib group, of whom 9% discontinued treatment, and 6% of patients in the crizotinib group, of whom 7% discontinued treatment.

The safety profile is “very reassuring, so we’re talking about a very effective, safe and easy-to-administer drug because we’re only administering once a day,” Dr. Selvaggi said. Based on the “robust” data, he said the company will start discussions with FDA this month.