ELCC 2017 News: Ensartinib Demonstrates CNS Activity in ALK-positive NSCLC Patients

Ensartinib is taken forward to phase III trial based on phase I/II results

Ensartinib demonstrated intracranial responses in patients with ALK-positive non–small-cell lung cancer (NSCLC) and central nervous system (CNS) metastases, according to findings presented on 6 May, 2017, at the European Lung Cancer Conference (ELCC) in Geneva, Switzerland.

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

The multicentre phase I/II study of ensartinib enrolled 26 patients with ALK-positive NSCLC and asymptomatic CNS metastases at baseline, with or without systemic disease (13DEC16 listings). Patients with only CNS disease were required to have at least 1 measurable target lesion ≥ 3 mm in diameter. The study enrolled ALK TKI naive patients and also patients that had received prior crizotinib and/or a second generation ALK TKI.

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 RANO criteria.

CNS response observed in all groups of patients, including those with and without baseline target lesions

ELCC 2017 Abstract 88O

Best change from baseline in target CNS lesions.
Credit: Karen L. Reckamp

CNS responses were observed in all groups of patients, whether they were ALK TKI naive or had received prior treatment with crizotinib and/or a second generation ALK TKI. At baseline, 13 (50%) patients had CNS target lesions with or without non-target lesions and the other half had only CNS non-target lesions. The cohort with baseline CNS target lesions demonstrated an intracranial response rate (RR), assessed by the investigator, of 69%, including one complete response (CR). In addition, stable disease (SD) was observed in 31%, resulting in a 100% disease control rate (DCR). Among the patients with baseline target lesions, 3 were ALK TKI naive; the intracranial RR in these patients was 100%. Of the 8 patients with target lesions who had received prior crizotinib only, the intracranial RR was 62%, and in the 2 patients having received crizotinib and a prior second generation ALK TKI, one achieved PR and one had SD.

In the cohort of 13 patients with only non-target CNS lesions at baseline, one 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 non-target lesions) was 5.8+ months. The longest duration of intracranial response was 24 months.

The ensartinib clinical data supported preclinical findings

Animal studies had shown that administration of ensartinib at the therapeutic dose yielded a CNS concentration that was 4 times higher than the 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 harbours the F1174L mutation.


The authors concluded that their clinical findings supported the preclinical results, which indicated that that the use of ensartinib may result in favourable 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.

Discussant point: Sanjay Popat, consultant medical oncologist from the Royal Marsden Hospital and who discussed the study results, said that ensartinib showed impressive initial intracranial activity. In term of unanswered questions for ALK-positive advanced NSCLC he underlined one in particular, if there are any meaningful intracranial efficacy differences between next generation ALK TKIs. Currently, in the EU,  relevant research questions seem to be which is the optimal next generation ALK TKI post crizotinib and does ALK genotype matter; he emphasised that prospective genotype-directed data are required. In the US, the following practice relevant questions matter: how much are better next generation ALK TKIs over first-line crizotinib and should next generation ALK TKIs be given up front.


Trial funding from Xcovery Holding Company was disclosed.


88O K.L. Reckamp, et al. CNS activity of ensartinib in ALK+ non-small cell lung cancer (NSCLC) patients (pts).