Ensartinib is a potent ALK small molecule tyrosine kinase inhibitor (TKI). It has shown efficacy in intracranial tumor models. The activity of ensartinib is being evaluated in an ongoing phase 2 study of ALK positive NSCLC patients (pts). As progression due to growth of pre-existing brain metastases (BrM) or development of new BrM is a common mechanism of treatment resistance, we examined the clinical intracranial activity of ensartinib in pts with known BrM (target and/or non-target) at baseline or subsequent central nervous system (CNS) progression.
Pts who were either ALK TKI naïve (1st line), had received prior crizotinib and no other ALK TKI (2nd line), or had received prior crizotinib and a 2nd generation ALK TKI (3rd line) received ensartinib 225mg QD until disease progression (PD), unacceptable toxicity or investigator discretion. Tumor assessments were performed locally every 8 weeks. Pts with asymptomatic BrM at baseline were allowed to enroll. To be considered a CNS target lesion, it had to be > 3 mm in diameter and, if previously treated, must have been at least 4 weeks post whole brain radiation therapy with demonstrated tumor growth and may not have been treated by stereotactic radiosurgery.
As of the data cut-off (May 1, 2018), 77 ALK evaluable pts (ALK+ NSCLC pts at > 200mg QD with a post baseline response assessment) were assessed. Overall, 23 pts (30%) had BrM progression (new or existing lesions). For 41 pts who had no BrM at baseline and received ensartinib as 1st line (10 pts), 2nd line (18 pts) or 3rd line (13 pts), only 2 pts (5%) progressed due to the development of BrM. For 36 pts who had BrM at baseline (5 as 1st line, 19 as 2nd line, 12 as 3rd line), 21 pts (58 %) had BrM progression, some at the time of systemic progression. For patients with baseline CNS target lesions, the CNS objective response rate was 100% (n = 3) for 1st line pts, 54% (n = 13) for 2nd line pts, and 33% (n = 3) for 3rd line pts; with a CNS disease control rate of 100% for all pts. Complete CNS responses were observed in 3 pts with target CNS lesions and in 3 pts with only non-target lesions.
The data indicate that ensartinib has promising CNS activity.
Clinical trial identification
Legal entity responsible for the study
Xcovery Holdings, Inc.
Has not received any funding.
H. Wakelee: Research support: Pfizer, Novartis, Xcovery. K.L. Reckamp: Research funds to institution: Xcovery; Consultant and research funds to institution: Ariad. T.A. Leal: Consultant: Takeda, AstraZeneca, Novartis, AbbVie, BMS. G. Blumenschein: Consultant: BMS, Bayer, Clovis, Merck, Celgene, AbbVie, Novartis; Research support: Xcovery, AstraZeneca. E. Shum: Consulting work: Boehringer Ingelheim. J. Nieva: Research support: Merck; Consultant: Genentech and AstraZeneca; Shareholder: Epic Sciences. G. Oxnard: Consulting: Takeda and Ignyta. R.E. Sanborn: Institutional support: Bristol‐Meyers Squibb and Medimmune; Research support: Merck (investigator‐initiated trial); Advisory boards: Peregrine Pharmaceuticals, Seattle Genetics; travel to research related meetings: Bristol‐Meyers Squibb, Five Prime Therapeutics. G. Dukart, K. Harrow, C. Liang, A. Holzhausen: Full time employee and stock options: Xcovery Holdings, Inc. L. Horn: Consulting: Xcovery Holding Company, BMS, BI, Abbvie, Genentech, Merck. All other authors have declared no conflicts of interest.