Ensartinib in advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, two-staged, phase 1 trial

Abstract

Background: Ensartinib, a potent second-generation tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET and ROS1, was evaluated in a phase I clinical trial in patients with advanced, ALK-rearranged non-small cell lung cancer (NSCLC).

Methods: Patients with advanced, ALK or ROS1-positive NSCLC were recruited from 2 centers in China. This study consisted of dose escalation and expansion stages. Patients were treated with oral ensartinib [dosage of escalation stage was from 150, 200, 225 to 250 mg per day, expansion stage was recommended phase II dose (RP2D)] in continuous 28-day cycles. The primary objectives were safety, dose limited toxicity (DLT), maximum tolerated dose (MTD), and RP2D based on tolerability. Key secondary objectives included pharmacokinetic (PK) and anti-tumor activity.

Results: Forty-eight patients were enrolled, 37 (77.1%) were ALK TKI-naïve, 11 (22.9%) patients had previously received crizotinib, ceritinib or alectinib. Ensartinib was well tolerated and common treatment-related adverse events (TRAEs) included rash (87.5%), transaminase elevation (60.4%), pruritus (45.8%) and creatinine elevation (35.4%). The top 3 grade 3-5 TRAEs were rash (14.6%), elevated alanine aminotransferase (ALT) (12.5%) and aspartate transaminase (AST) (4.2%). Two DLTs were observed in 250 mg, so MTD and RP2D was 225 mg per day. Ensartinib was moderately absorbed (median Tmax: 3.00-4.00 h) and slowly eliminated (mean T1/2: 21.0-30.2 h). The area under the curve (AUC) of ensartinib reached saturation at 200 to 225 mg and no major accumulation after daily administration. For all patients, the objective response rate (ORR) and disease control rates (DCR) were 64.6 % and 81.3%, median progression-free survival (mPFS) was 16.79 months. In subgroup analysis, the ORR and mPFS was 81.3% and 45.5%, 25.73 and 4.14 months in TKI-naïve and -treated ALK+ patients, respectively. The intra-cranial ORR and mPFS for patients with measurable brain metastases were 66.7% and 22.90 months. ALK abundance may predict the efficacy of ensartinib. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed specific signaling pathways enrichment in long and short progression-free survival (PFS) groups.

Conclusions: Ensartinib was well tolerated under 225 mg (MTD) and demonstrated promising anti-tumor activity in ALK+ NSCLC patients, including those with CNS metastases and those previously TKI-treated.

Trial registration: ClinicalTrials.gov NCT02959619.

Keywords: Ensartinib; anaplastic lymphoma kinase (ALK); central nervous system metastases (CNS metastases); non-small cell lung cancer (NSCLC); phase I study.

Figure 1

Patient flow diagram. PD, progressive disease.

Figure 2

Mean plasma concentration time curve (linear graph) of different dose groups of ensartinib in single dose and multiple dose cohorts. (A) Single dose time-concentration Curve. (B) Multiple dose time-concentration curve.

Figure 3

Time on treatment and maximum reduction of target lesions for patients in the 150- to 250-mg dose cohorts. (A) Time on treatment for patients in the 150- to 250-mg dose cohorts. All data were cut off on December 31, 2020. (B) Maximum reduction of target lesions from baseline for patients in the 150- to 250-mg dose cohorts. The best response for target lesions per patient was determined on the basis of RECIST v1.1 criteria. *, patients who reported baseline brain metastasis; **, brain metastasis as target lesion. PR, partial response; CR, complete response; SD, stable disease; PD, progressive disease; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor; PFS, progression free survival.

Figure 4

The baseline mutational profile and PFS in the group with high or low ALK fusion abundance. (A) The baseline mutational profile. All the genes with nonsynonymous mutations are displayed. (B) Kaplan-Meier estimate of progression-free-survival in the group with high ALK fusion abundance and group with low ALK fusion abundance. PFS, progression-free survival; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor; ECOG, Eastern Cooperative Oncology Group; CR, complete response; PR, partial response; PD, progression disease; SD, stable disease.