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ELCC 2017: Ensartinib Demonstrates CNS Activity in ALK-Positive NSCLC

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Key Points

  • CNS responses were observed in all groups of patients, whether they were ALK tyrosine kinase inhibitor–naive or had received prior treatment with crizotinib and/or a second-generation ALK tyrosine kinase inhibitor.
  • The cohort with baseline CNS target lesions demonstrated an intracranial response rate, assessed by the investigator, of 69%, including one complete response. In addition, stable disease was observed in 31%, resulting in a 100% disease control rate.
  • Of the eight patients with target lesions who had received prior crizotinib only, the intracranial response rate was 62%, and in the two patients having received crizotinib and a prior second-generation ALK tyrosine kinase inhibitor, one achieved partial response and one had stable disease.

Ensartinib demonstrated intracranial responses in patients with anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC) and central nervous system (CNS) metastases, according to findings presented by Reckamp et al at the 2017 European Lung Cancer Conference (ELCC) in Geneva, Switzerland (Abstract 88O).

Lead author Karen L. Reckamp, MD, medical oncologist at City of Hope, explained that ensartinib (X-396) is a potent small molecule tyrosine kinase inhibitor that has activity against ALK, but also targets MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK.

Study Details

The multicenter phase I/II study of ensartinib enrolled 26 patients with ALK-positive NSCLC and asymptomatic CNS metastases at baseline, with or without systemic disease. Patients with only CNS disease were required to have at least one measurable target lesion ≥ 3 mm in diameter. The study enrolled ALK tyrosine kinase inhibitor–naive patients, and also patients that had received prior crizotinib and/or a second-generation ALK tyrosine kinase inhibitor.

All 26 patients received ensartinib orally at ≥ 200 mg daily on a continuous 28-day schedule, and the 225-mg dose was the dose determined for further evaluation. Overall and systemic response was assessed using RECIST v1.1, and the CNS response was assessed by modified Response Assessment in Neuro-Oncology criteria.

Findings

CNS responses were observed in all groups of patients, whether they were ALK tyrosine kinase inhibitor–naive or had received prior treatment with crizotinib and/or a second-generation ALK tyrosine kinase inhibitor. At baseline, 13 (50%) patients had CNS target lesions with or without nontarget lesions and the other half had only CNS nontarget lesions. The cohort with baseline CNS target lesions demonstrated an intracranial response rate (RR), assessed by the investigator, of 69%, including one complete response. In addition, stable disease (SD) was observed in 31%, resulting in a 100% disease control rate. Among the patients with baseline target lesions, three were ALK tyrosine kinase inhibitor–naive; the intracranial RR in these patients was 100%. Of the eight patients with target lesions who had received prior crizotinib only, the intracranial RR was 62%, and in the two patients having received crizotinib and a prior second-generation ALK tyrosine kinase inhibitor, one achieved PR and one had SD.

In the cohort of 13 patients with only nontarget CNS lesions at baseline, 1 patient achieved CR and 8 patients showed SD.

The median duration of response among the 10 responding patients (9 with target lesions and 1 with only nontarget lesions) was 5.8+ months. The longest duration of intracranial response was 24 months.

Animal studies had shown that administration of ensartinib at the therapeutic dose yielded a CNS concentration that was four times higher than the half maximal inhibitory concentration (IC50) for growth inhibition of ALK-positive cells in vitro.

In addition, ensartinib was significantly more effective than crizotinib at inhibiting intracranial growth in the SH-SY5Y neuroblastoma model, which harbors the F1174L mutation.

Conclusions

The authors concluded that their clinical findings supported the preclinical results, which indicated that that the use of ensartinib may result in favorable therapeutic outcomes in patients with ALK-positive NSCLC and CNS metastases. The authors noted that a CNS response was observed in all groups of treated patients.

Ensartinib is being further evaluated in the ongoing phase III eXalt3 trial, which, among other endpoints, is comparing the CNS response rate and time to CNS progression with ensartinib to crizotinib in the first-line setting for patients with ALK-positive NSCLC.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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