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Ensartinib shows CNS response in ALK-positive NSCLC

Christina Lau
18 days ago

Ensartinib, a small-molecule ALK tyrosine kinase inhibitor (TKI), has demonstrated intracranial response in patients with ALK-positive non-small-cell lung cancer (NSCLC) with central nervous system (CNS) metastases.

In a multicentre phase I/II study that included 26 patients with ALK-positive NSCLC and asymptomatic CNS metastases at baseline, ensartinib treatment resulted in CNS responses regardless of whether patients were ALK-TKI–naïve or had received prior treatment with crizotinib and/or a second-generation ALK-TKI. [ELCC 2017, abstract 88O]

“Among 13 patients with baseline CNS target lesions, intracranial response rate as assessed by investigator was 69 percent, including one complete response. Stable disease was observed in 31 percent of patients, resulting in a disease control rate of 100 percent,” reported lead author Dr Karen Reckamp of City of Hope, Duarte, California, US.

“Three patients with baseline target lesions were ALK-TKI–naïve, and their intracranial response rate was 100 percent,” she continued. “Among eight patients with baseline target lesions previously treated with crizotinib, intracranial response rate was 62 percent. In the two patients who had received prior treatment with crizotinib and a second-generation ALK-TKI, one patient achieved partial response and one had stable disease.”

In the other 13 patients with nontarget CNS lesions at baseline, one patient achieved complete response, while eight had stable disease.

Among the 10 responders (nine with target lesions, one with nontarget lesions), the median duration of response exceeded 5.8 months, with the longest duration of intracranial response being 24 months.

“Ensartinib is a potent small-molecule ALK-TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK,” explained Reckamp. “In animal studies, CNS concentration of ensartinib at the therapeutic dose was four times higher than the inhibitory concentration 50 percent [IC50] for growth inhibition of ALK-positive cells in vitro. Furthermore, ensartinib was significantly more effective than crizotinib at inhibiting intracranial growth of a SH-SY5Y neuroblastoma model harbouring the F1174L mutation.”

Patients in the study received ensartinib orally at a dosage of ≥200 mg daily on a continuous 28-day schedule. The 225 mg daily dose was subsequently selected for further evaluation.

While the study included patients with or without systemic disease, patients with CNS disease only were required to have at least one measurable target lesion ≥3 mm in diameter.

“Our findings suggest that use of ensartinib may result in favourable outcomes in patients with ALK-positive NSCLC with CNS metastases,” said Reckamp. “The ongoing phase III eXalt3 trial is comparing CNS response rate and time to CNS progression with ensartinib vs crizotinib as first-line treatment for ALK-positive NSCLC.”

“One unanswered question in the treatment of ALK-positive NSCLC is whether there are meaningful differences in intracranial efficacy between next-generation ALK-TKIs,” commented Dr Sanjay Popat of the Royal Marsden Hospital, London, UK. “Prospective genotype-directed data are needed to address the questions of which next-generation ALK-TKI to use after crizotinib, and whether ALK genotype matters. Another question is whether next-generation ALK-TKIs should be used upfront.”  

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