FDA Accepts NDA for Ensartinib in Metastatic ALK-Positive NSCLC

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The regulatory agency set an action date of December 28, 2024 for ensartinib as a treatment for those with ALK-positive non–small cell lung cancer.

“Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC,” according to the authors of the phase 3 eXalt3 trial (NCT02767804).

“Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC,” according to the authors of the phase 3 eXalt3 trial (NCT02767804).

The FDA has accepted a new drug application (NDA) for ensartinib as a treatment for adult patients with metastatic ALK-positive non–small cell lung cancer (NSCLC), according to a press release from Xcovery Holdings, which develops the agent jointly with Betta Pharmaceuticals.1

The regulatory agency has set a Prescription Drug User Fee Act date of December 28, 2024 for its decision on approving ensartinib in the aforementioned indication.

Supporting data for the NDA came from the phase 3 eXalt3 trial (NCT02767804). According to findings published in JAMA Oncology, the median progression-free survival (PFS) was 25.8 months (range, 0.03-44.0) in patients who received ensartinib vs 12.7 months (range, 0.03-38.6) in those who were treated with crizotinib (Xalkori; HR, 0.51; 95% CI, 0.35-0.72; P <.001).2

Additionally, the confirmed objective response rate (ORR) in each respective treatment arm was 74% (95% CI, 66%-81%) vs 67% (95% CI, 58%-74%), and the median duration of response (DOR) among responders was not reached (NR; 95% CI, 22.0 months-NR) vs 27.3 months (95% CI, 12.9-NR).

Data from a blinded independent review committee showed that the intracranial response rate with ensartinib was 63.6% compared with 21.1% with crizotinib for those who had target brain metastases at baseline.

Investigators highlighted treatment-related serious adverse effects (AEs) in 7.7% of patients who were treated with ensartinib compared with 6.1% of those who received crizotinib. Toxicities of this kind in the ensartinib arm included rash (n = 3) and liver toxic effects (n = 3). Additionally, 9.1% and 6.8% of patients discontinued treatment with ensartinib and crizotinib, respectively, due to treatment-related AEs.

“Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC,” Leora Horn, MD, MS, global clinical head for lung cancer and lung cancer strategy at AstraZeneca, and study coauthors wrote.2 “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.”

In the open-label, multicenter, randomized phase 3 eXalt3 trial, 290 patients were randomly assigned 1:1 to receive ensartinib at 225 mg once a day (n = 143) or crizotinib at 250 mg twice a day (n = 147).

The trial’s primary end point was PFS in the intent-to-treat population based on blinded independent review committee assessment using RECIST v1.1 criteria. Secondary end points included overall survival, central nervous system (CNS) response rate, and CNS time to progression.

Patients 18 years and older who had advanced/recurrent or metastatic NSCLC that is ALK positive and measurable disease according to RECIST v1.1 guidelines were able to enroll on the trial. Those with asymptomatic brain metastases were eligible for enrollment, as were patients who received 1 prior line of chemotherapy for metastatic disease.

The median age was 54 years (range, 25-86) in the ensartinib arm and 53 years (range, 26-90) in the crizotinib arm. In each respective arm, most patients were 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%). Additionally, 23.8% and 28.6% of patients in each respective arm received prior chemotherapy.

“The FDA’s acceptance of this NDA represents a key milestone for Xcovery in its mission to bring ensartinib as a novel and distinct first-line therapeutic option to [patients with] ALK-positive NSCLC,” Giovanni Selvaggi, MD, chief medical officer at Xcovery, stated in the press release.1 “We will continue to work closely with the agency during the review period.”

References

  1. 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
  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
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