Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study
Leora Horn, Jeffrey R Infante, Karen L Reckamp, George R Blumenschein, Ticiana A Leal, Saiama N Waqar, Barbara J Gitlitz, Rachel E Sanborn, Jennifer G Whisenant, Liping Du, Joel W Neal, Jon P Gockerman, Gary Dukart, Kimberly Harrow, Chris Liang, James J Gibbons, Allison Holzhausen, Christine M Lovly, Heather A Wakelee, Leora Horn, Jeffrey R Infante, Karen L Reckamp, George R Blumenschein, Ticiana A Leal, Saiama N Waqar, Barbara J Gitlitz, Rachel E Sanborn, Jennifer G Whisenant, Liping Du, Joel W Neal, Jon P Gockerman, Gary Dukart, Kimberly Harrow, Chris Liang, James J Gibbons, Allison Holzhausen, Christine M Lovly, Heather A Wakelee
Abstract
Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR.
Conflict of interest statement
Conflicts of Interest: HAW is a consultant for Peregrine Pharmaceuticals, Helsinn Therapeutics, ACEA Biosciences, and Pfizer, has received an honorarium or travel accommodations from Peregrine Pharmaceuticals, Biocon, ACEA Biosciences, Helsinn Therapeutics, Genentech/Roche, Pfizer, and Novartis, and has research support from Genentech/Roche, Pfizer, Lilly, Celgene, AstraZeneca/MedImmune, Exelixis, Novartis, Clovis Oncology, Xcovery, Bristol-Myers Squibb, Gilead Sciences, Pharmacyclics, and ACEA Biosciences. KLR is a consultant for Amgen, Boehringer Ingelheim, ARIAD, Astellas Pharma, Nektar, and Euclises. GB is a consultant for Bristol-Myers Squibb, Bayer, Celgene, Clovis Oncology, Abbvie, ARIAD, AstraZeneca, and Merck, has received an honorarium from Abbvie/Genentech, Bayer, Bristol-Myers Squibb, and Celgene, and has research funding from Merck, AstraZeneca, Celgene, Abbvie, Genentech, Xcovery, Novartis, Bayer Schering Pharma, Bristol-Myers Squibb, and GlaxoSmithKline. TAL is a consultant for ARIAD, Genentech/Roche, and Takeda, and has received travel accommodations from Genentech/Roche, Xcovery, and Takeda. BG is a consultant for AstraZeneca, ARIAD, and Genentech, is part of a speakers’ bureau for Genentech and Lilly, and has research funding from Ignyta, AstraZeneca, and Xcovery. RES is a consultant for Amgen, Seattle Genetics, Peregrine Pharmaceuticals, ARIAD, Genentech/Roche, AstraZeneca, and Celldex, has received an honorarium or travel accommodations from AstraZeneca and Five Prime Therapeutics, and has research funding from Merck. JWN is a consultant for Clovis Oncology, Boehringer Ingelheim, ARMO BioSciences, Nektar, ARIAD/Takeda, and CARET, and has research funding from Genentech/Roche, Merck, ArQule, Novartis, Boehringer Ingelheim, Nektar, and Exelixis. JPG is employed at Novella Clinical. GD is a consultant, has stock or other ownership, and has received travel accommodations from Xcovery and Tyrogenex, and is part of an intellectual property agreement albeit without financial interests with Wyeth/Pfizer. KH is employed, has stock or other ownership, and has received travel accommodations from Xcovery and Tyrogenex. CL is employed in a leadership role and has stock or other ownership in Xcovery and Tyrogenex. JJG is employed with Xcovery and has stock or other ownership with Pfizer. AH is employed at Xcovery. CML is a consultant for ARIAD, Clovis Oncology, Genoptix, and Novartis, has research funding from AstraZeneca and Novartis, and has received an honorarium or travel accommodations from Novartis, Sequenom, Qiagen, Pfizer, and NCCN. LH is a consultant for Bristol-Myers Squibb, Xcovery, Genentech, Abbvie, Merck, and AstraZeneca. All remaining authors have no conflicts to disclose.
©2018 American Association for Cancer Research.
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Source: PubMed