Ensartinib may be a viable treatment option for some forms of secondary ALK alterations.
ALK rearrangement occurs in approximately 5% of non–small-cell lung cancers (NSCLCs). Ensartinib is a small-molecule ALK tyrosine kinase inhibitor (TKI) that has potently inhibited wild-type ALK and the most common crizotinib-resistant mutations, including F1174, C1156Y, G1269A, L1196M, S1206R, and T1151, in enzymatic assays. In a single-arm, open-label phase 2 study, researchers evaluated the efficacy and safety of ensartinib, as well as associations between ensartinib efficacy and ALK resistance mutations in patients with crizotinib-refractory, advanced, ALK-positive NSCLC.
A total of 156 patients in the full analysis set were treated with ensartinib 225 mg once daily. The primary end point was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours version 1.1. Secondary end points included disease control, central nervous system (CNS) responses, duration of intracranial response, intracranial progression-free survival (PFS), time to first intracranial response, and duration of intracranial response.
Of the 147 patients with an evaluable assessment, 76 (52%; 95% confidence interval [CI], 43%-60%) had an objective response (all were confirmed partial response); 137 (93%; 95% CI, 88%-97%) had disease control (partial response or stable disease); and 41% had stable disease. Tumor burden was reduced from baseline in 121 (82%) of 147 patients. Median PFS in the full analysis set was 9.6 months (95% CI, 7.4-11.6). In patients with measurable brain metastases (N = 40), 70% had an objective response and 28% had stable disease. The median time to first response was 1.3 months (95% CI, 1.2-1.4). The median intracranial duration of response was 8.6 months (95% CI, 6.4 months-not reached).
Response was also measured according to the type of crizotinib resistance mechanism; ORRs were 44% among 45 patients with secondary ALK alterations, 57% among 75 patients with detectable ALK fusions, and 57% among 98 patients with no detectable resistance mechanisms. Tumors with the ALK F1174L/V (N = 7), C1156Y (N = 7), G1269A (N = 6), and T1151 (N = 3) secondary resistance mutations were particularly sensitive to ensartinib, showing similar ORRs of 71%, 71%, 67%, and 67%, respectively. However, response to ensartinib was minimal in patients with alterations in genes that could mediate bypass signaling pathways (eg, EGFR, KRAS, PIK3CA, and ERBB2).
The majority of treatment-related adverse events were grade 1 or 2. The most common grade 3 adverse events were rash (6%), increased alanine aminotransferase (6%), facial edema (4%), and increased aspartate aminotransferase (3%); no patients experienced a grade 4 event.
The researchers concluded that ensartinib demonstrates unique activity against several secondary ALK mutations, including common ceritinib-resistant and alectinib-resistant mutations, and could expand treatment options for patients who are intolerant to other ALK-TKIs.
Reference
Yang Y, et al. Lancet Respir Med. 2020;8:45-53.
