Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study

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.

Figures

Figure 1. CONSORT Diagram

Clinical trial flow diagram that depicts the number of patients that were consented, received study therapy in both dose escalation and expansion, and evaluable for safety and response. The diagram also depicts the number of pharmacokinetic samples analyzed.

Figure 2. Waterfall plot of best systemic response

Best percentage change from baseline in sum of target lesions is presented for the ALK-positive evaluable patients at ≥200 mg enrolled on study. Dashed lines are RECIST v1.1 criteria for partial response and progressive disease. Thirty-six patients (of 60) had a partial response and 80% had tumor regression. The navy bars are those patients that were ALK TKI-naïve, while the yellow bars represent those patients that had prior crizotinib therapy only, and the light blue bars represent those patients that had prior crizotinib and a second-generation ALK TKI. *Denotes those patients with progressive disease as the best overall response. >Denotes patients still on study at the time of data cutoff. (Note: Two patients had incomplete follow-up scans, therefore a change in tumor size is not available.)

Figure 3. Waterfall plot of best CNS response

Best intracranial percentage change from baseline in target CNS lesions is presented for the ALK-positive evaluable patients at doses ≥200 mg enrolled on study. Dashed lines indicate RECIST v1.1 cut-offs for partial response and progressive disease. Of the 14 patients with target CNS lesions, two complete responses were observed, seven had a partial response, and four had stable disease. The navy bars are those patients that were ALK TKI-naïve, while the yellow bars represent those patients that had prior crizotinib therapy only, and the light blue bars represent those patients that had prior crizotinib and a second-generation ALK TKI. *Denotes those patients with progressive disease as the best intracranial response. >Denotes patients still on study at the time of data cutoff.

Figure 4. Progression-free survival curves

Kaplan-Meier estimate of progression-free survival (PFS) with 95% confidence intervals for all ALK-positive, evaluable NSCLC patients that received ≥200 mg of ensartinib, where the median PFS was 9.2 months (A). Kaplan-Meier estimates of PFS are also shown for those ALK-positive, evaluable patients who were ALK TKI-naïve (red line), received prior crizotinib only (green line), and received prior crizotinib and a 2nd generation inhibitor (blue line), where the median PFS for those groups was 26.2 months, 9.0 months, and 1.9 months, respectively (B).