FDA Approves Ensartinib in Metastatic ALK-Positive NSCLC

Data from the phase 3 eXalt3 trial support the approval of ensartinib in adult patients with metastatic ALK-positive non–small cell lung cancer.

The News

The FDA has approved ensartinib (Ensacove) as a treatment for adult patients with metastatic or locally advanced ALK-positive non–small cell lung cancer (NSCLC), according to a news release from the FDA.¹

Supporting Data

The approval for ensartinib was supported by findings from the phase 3 eXalt3 trial (NCT02767804), in which investigators evaluated the agent in adult patients with ALK-positive NSCLC vs crizotinib (Xalkori).

Topline data showed a median progression-free survival (PFS) of 25.8 months (95% CI, 21.8-not estimable [NE]) with ensartinib vs 12.7 months (95% CI, 9.2-16.6) with crizotinib (HR, 0.56; 95% CI, 0.40-0.79; P = .0007). Overall survival (OS) outcomes did not significantly differ between arms (HR, 0.88; 95% CI, 0.63-1.23; P = 4570).

Additional findings were published in JAMA Oncology.²

A confirmed objective response rate (ORR) benefit was observed with ensartinib at 74% (95% CI, 66%-81%) vs 67% (95%, 58%-74%) with crizotinib. Within the modified ITT group, the rates were 75% (95% CI, 66.5%-82.6%) and 68% (95% CI, 58.5%-75.5%), respectively. Additionally, the median duration of response (DOR) in the respective arms were not reached (NR; 95% CI, 22.0 months-NR) vs 27.3 months (95% CI, 12.9-NR) across the ITT population.

Blinded independent review committee (BICR) data showed an intracranial response rate of 63.6% with ensartinib vs 21.1% with crizotinib for patients with target brain metastases at baseline. Furthermore, among patients with brain metastases at baseline, the median PFS was 11.8 months (95% CI, 5.5-NR) with ensartinib vs 7.5 months (95% CI, 5.5-9.3) with crizotinib (HR, 0.55; 95% CI, 0.30-1.01; P = .05).

At 12 months, 4.2% of the ensartinib group and 23.9% of the crizotinib arm had developed brain metastases (HR, 0.32; 95% CI, 0,16-0.63; P = .001). At 36 months, 61% vs 25% of the respective groups were disease free.

Among patients not previously treated with chemotherapy, the median PFS was not reached (95% CI, 20.2-NR) in the ensartinib arm and 11.1 months (95% Ci, 7.8-16.6) in the crizotinib arm. For patients who had received prior chemotherapy, median PFS was 22.0 months (95% CI, 10.9-NR) vs 12.8 months (95% CI, 5.5-NR) in each respective arm.

Across the modified ITT group, 30 patients in the ensartinib group and 32 in the crizotinib group died (HR, 0.91; 95% CI, 0.54-1.54), with median overall survival (OS) not reached in either group.

Expert Perspective

“Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC. In this randomized clinical trial, ensartinib showed superior systemic and intracranial efficacy compared with crizotinib and an overall favorable safety profile that is distinct from that of other agents in this class. A more precise understanding of primary and acquired resistance mechanisms is warranted to establish the optimal sequence of ensartinib and other available second- and third-generation ALK inhibitors in the first-line setting,” Leora Horn, MD, MS, and eXalt3 study co-authors wrote in the publication.²

Horn is the vice president and global clinical head for clinical development and late oncology at AstraZeneca.

eXalt3 Trial Design

In the trial, the primary end point was PFS in the ITT population assessed by BICR according to RECIST v1.1 criteria. Key secondary end points included OS, central nervous system (CNS) response rate, and BICR assessed CNS time to progression.

A total of 290 patients 18 years or older with advanced, recurrent, or metastatic ALK-positive NSCLC were enrolled and randomly assigned 1:1 to receive ensartinib (n = 143) or crizotinib (n = 147).

Stratification of patients was based on prior chemotherapy treatment, ECOG performance status, CNS metastases, and geographic region. Treatment in respective groups included 225 mg of daily oral ensartinib or 250 mg of crizotinib twice daily. Additionally, 32.9% (n = 47) and 38.8% (n = 57) of the ensartinib and crizotinib groups had brain metastases at baseline.

The modified ITT population consisted of 247 patients randomly assigned based on local ALK testing results with central confirmation (n = 112) or positive central ALK testing (n = 135). Among the 43 patients excluded from the ITT population, 27 had insufficient samples, 7 had uninterpretable findings, and 9 had negative local ALK test results. The ITT cohorts consisted of 121 patients receiving ensartinib and 126 receiving crizotinib.

In the ensartinib arm, the median age was 54 years (range, 25-86) vs 53 years (range, 26-90) in the crizotinib arm. In the respective arms, patients were predominately male (50.3% vs 52.4%), Asian (53.8% vs 57.1%), had an ECOG performance status of 0 or 1 (95.1% vs 95.2%), never smoked (59.4% vs 63.9%), and had stage IV disease (90.9% vs 93.2%). Furthermore, prior chemotherapy was received in 23.8% and 28.6% of the respective arms.

Safety Data

The only reported grade 3 and 4 adverse events (AEs) in the ensartinib group were increased bilirubin level, increased creatin phosphokinase level, and hyponatremia.

Dose reduction related to treatment-related AEs occurred in 23.8% (n = 34) and 19.9% (n = 29) of the ensartinib and crizotinib groups. AEs leading to treatment discontinuation with ensartinib included increased liver enzymes (n = 12), pneumonitis (n = 2), chest pain (n = 1), and pyrexia (n = 1). No treatment-related deaths were reported in either group.

Notable ensartinib-related AEs included rash (67.8%), elevated alanine aminotransferase (48.3%), elevated aspartate aminotransferase (37.8%), nausea (22.4%), edema (21.0%), and constipation (20.3%). Furthermore, grade 3 rash occurred in 11.2% of patients and was managed by dose reduction, interruption, and reduction. The median duration of grade 3 rash was 18 days.

The FDA previously accepted a new drug application for ensartinib to treat adult patients with metastatic ALK-positive NSCLC in March 2024.³

References

1. FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer. News release. FDA. December 18, 2024. Accessed December 18, 2024. https://tinyurl.com/yy8e6bd6
2. Horn L, Wang Z, Wu G, et al. Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer: a randomized clinical trial. JAMA Oncol. Published online September 2, 2021. doi:10.1001/jamaoncol.2021.3523
3. U.S. Food and Drug Administration (FDA) has accepted the new drug application (NDA) for ensartinib. News release. Xcovery Holdings, Inc. March 13, 2024. Accessed March 15, 2024. https://tinyurl.com/ydkezep6