Ensartinib could expand treatment options for ALK-positive NSCLC
medwireNews: At least half of patients with crizotinib-resistant ALK translocation-positive non-small-cell lung cancer (NSCLC) respond to treatment with the new-generation ALK inhibitor ensartinib, including those with brain metastases, phase II study data show.
Writing in The Lancet Respiratory Medicine, Li Zhang (Sun Yat-sen University Cancer Center, Guangzhou, China) and colleagues say: “Taken together with the promising efficacy reported in the previous phase 1 and 2 study of ensartinib, our findings suggest that ensartinib could be an effective treatment option for patients with disease progression on crizotinib.”
Zhang and team found that 52% of 147 patients with stage IIIb or IV ALK-positive NSCLC that had progressed during crizotinib therapy had an objective response (all partial responses) to treatment with oral ensartinib 225 mg/day given on a continuous dosing schedule. A further 41% had stable disease.
In addition, among the 40 patients with measurable brain metastases, the objective response rate (ORR) was 70%, and the stable disease rate 28%.
When the investigators measured response according to the type of crizotinib resistance mechanism present, they found that the ORR was 44% among the 45 patients with secondary ALK alterations, 57% among the 75 with detectable ALK fusions, and 57% among the 98 with no detectable resistance mechanisms.
Of note, tumors with the ALK F1174 (n=7), C1156Y (n=7), G1269A (n=6), and T1151 (n=3) secondary resistance mutations were particularly sensitive to ensartinib, with ORRs of 71%, 71%, 67%, and 67%, respectively.
Conversley, the response to ensartinib was generally nonexistent in the very small number of patients with alterations in genes that could mediate bypass signaling pathways (eg, EGFR, KRAS, PIK3CA, and ERBB2).
“This finding suggests that identification of resistant mechanisms in patients with disease progression while on crizotinib is crucial to optimisation of subsequent treatment choices,” Zhang et al remark.
Median progression-free survival in the total study population was 9.6 months, which compares favorably with other second- and third-generation ALK inhibitors, namely ceritinib (5.7 months) alectinib (8.3 months), and brigatinib (12.9 months). The authors caution, however, that “direct comparisons of results are difficult because of differences in study design.”
The study also showed that ensartinib was generally well tolerated. Although 91% of patients had at least one treatment-related adverse event (AE), the majority were grade 1 or 2. The most common grade 3 AEs were rash (6%), increased alanine aminotransferase concentrations (6%), facial edema (4%), and increased aspartate aminotransferase concentrations (3%), and no patients experienced a grade 4 event.
These findings suggest that “ensartinib could expand the spectrum of activity of available second-generation ALK TKIs [tyrosine kinase inhibitors], which is important for sequential treatment strategies,” conclude Zhang and co-authors.
They add that “the distinct side-effect profile of ensartinib suggests that the drug could be a treatment option for patients who are intolerant to other ALK TKIs.”
By Laura Cowen
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