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Ref Type Journal Article
PMID (31628085)
Authors Yang Y, Zhou J, Zhou J, Feng J, Zhuang W, Chen J, Zhao J, Zhong W, Zhao Y, Zhang Y, Song Y, Hu Y, Yu Z, Gong Y, Chen Y, Ye F, Zhang S, Cao L, Fan Y, Wu G, Guo Y, Zhou C, Ma K, Fang J, Feng W, Liu Y, Zheng Z, Li G, Wu N, Song W, Liu X, Zhao S, Ding L, Mao L, Selvaggi G, Yuan X, Fu Y, Wang T, Xiao S, Zhang L
Title Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial.
Journal Vol Issue Date Pages Journal Short Title
The Lancet. Respiratory medicine 2019 Oct 15 45-53 Lancet Respir Med
URL
Abstract Text Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored.We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693.Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]).Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies.Betta Pharmaceuticals.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Ensartinib Ensartinib 45 8
Drug Name Trade Name Synonyms Drug Classes Drug Description
Ensartinib X-396 ALK Inhibitor 32 Ensartinib (X-396) is a small molecule inhibitor of ALK, which inhibits downstream signaling and potentially leads to decreased growth of ALK-expressing tumors (PMID: 21613408, PMID: 31628085).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK I1171T ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 50% (2/4, all partial responses) and stable disease in 50% (2/4) of patients with ALK-positive non-small cell lung cancer harboring ALK I1171T (n=3) or I1171S (n=1) (PMID: 31628085; NCT0321569). 31628085
ALK L1196M ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 25% (1/12, all partial responses) and stable disease in 67% (8/12) of patients with ALK-positive non-small cell lung cancer harboring ALK L1196M (PMID: 31628085; NCT0321569). 31628085
ALK amp ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 56% (5/9, all partial responses) and stable disease in 44% (4/9) of patients with ALK-positive non-small cell lung cancer with ALK amplification (PMID: 31628085; NCT0321569). 31628085
ALK I1171S ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 50% (2/4, all partial responses) and stable disease in 50% (2/4) of patients with ALK-positive non-small cell lung cancer harboring ALK I1171T (n=3) or I1171S (n=1) (PMID: 31628085; NCT0321569). 31628085
ALK C1156Y ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 71% (5/7, all partial responses) and stable disease in 29% (2/7) of patients with ALK-positive non-small cell lung cancer harboring ALK C1156Y (PMID: 31628085; NCT0321569). 31628085
ALK fusion lung non-small cell carcinoma sensitive Ensartinib Phase II Actionable In a Phase II trial, Ensartinib (X-396) treatment resulted in an objective response in 57% (43/75; all partial responses), and stable disease (SD) in 33% (25/75) of patients with crizotinib-refractory non-small cell lung cancer harboring an ALK fusion, with a response rate of 59% and SD rate of 31% in the 70 patients with EML4-ALK, and a response rate of 40% and SD rate of 60% in the 5 patients with non-EML4 ALK fusions (PMID: 31628085; NCT03215693). 31628085
ALK F1174V ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 71% (5/7, all partial responses) of patients with ALK-positive non-small cell lung cancer harboring ALK F1174L (n=5) or ALK F1174V (n=1) (PMID: 31628085; NCT0321569). 31628085
ALK L1152R ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 50% (2/4, all partial responses) and stable disease in 25% (1/4) of patients with ALK-positive non-small cell lung cancer harboring ALK L1152R (n=3) or L1152V (n=1) (PMID: 31628085; NCT0321569). 31628085
ALK G1202R ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 33% (2/6, all partial responses) and stable disease in 50% (3/6) of patients with ALK-positive non-small cell lung cancer harboring ALK G1202R (PMID: 31628085; NCT0321569). 31628085
ALK positive lung non-small cell carcinoma sensitive Ensartinib Phase II Actionable In a Phase II trial, Ensartinib (X-396) treatment resulted in an objective response in 52% (76/147; all partial responses), and disease control in 93% (137/147) of patients with crizotinib-refractory ALK-positive non-small cell lung cancer, and a median progression-free survival of 9.6 mo., and of the 97 patients with brain metastases, 41% (40) demonstrated a partial response, and of those, 28 (70%) had an intracranial response and 39 (98%) had intracranial disease control (PMID: 31628085; NCT03215693). 31628085
ALK F1174L ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 71% (5/7, all partial responses) of patients with ALK-positive non-small cell lung cancer harboring ALK F1174L (n=5) or ALK F1174V (n=1) (PMID: 31628085; NCT0321569). 31628085
EML4 - ALK lung non-small cell carcinoma sensitive Ensartinib Phase II Actionable In a Phase II trial, Ensartinib (X-396) treatment resulted in an objective response in 59% (41/70; all partial responses) and stable disease in 31% (22/70) of patients with crizotinib-refractory non-small cell lung cancer harboring EML4-ALK (PMID: 31628085; NCT03215693). 31628085
ALK L1152V ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 50% (2/4, all partial responses) and stable disease in 25% (1/4) of patients with ALK-positive non-small cell lung cancer harboring ALK L1152R (n=3) or L1152V (n=1) (PMID: 31628085; NCT0321569). 31628085