Treatment with brigatinib resulted in tumor shrinkage among patients with progressive non-small cell lung cancer (NSCLC) with ALK alterations after progression with other next-generation ALK tyrosine kinase inhibitors (TKIs), according to data from a phase 2 trial published in the Journal of Thoracic Oncology.1

Next-generation ALK TKIs are the first-line treatment for ALK-positive NSCLC; however, treatment resistance inevitably occurs. The purpose of this study was to determine if patients whose disease previously progressed with a next-generation ALK TKI would respond to brigatinib, also a next-generation ALK TKI.

The multicenter, single-arm, phase 2 trial treated 22 patients with brigatinib who had ALK-positive NSCLC that had progressed with a prior next-generation ALK TKI. Patients with known brain metastases were included. The primary endpoint was objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Tumor biopsy was required prior to enrollment and specimens were analyzed by next-generation sequencing; ctDNA levels from blood samples were also assessed.

At baseline, the median patient age was 55 years, the median number of previous therapies was 3 (range, 1-6), and the median number of prior ALK TKIs was 2 (range, 1-4). Brain metastases or central nervous system metastases were present among 11 and 8 patients, respectively.


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During a median follow-up of 22 months, the ORR was 40% with a median duration of 5.3 months. The median PFS was 7 months (95% CI, 4.6-10.1) among the entire cohort, and 6.3 months (95% CI, 3.3-not evaluable) among patients with baseline brain metastases. Median OS was not yet reached.

Tumor tissue analysis identified 6 of 10 evaluable samples with ALK resistance mutations, and 3 of these patients experienced a response with brigatinib. There were 7 of 13 evaluable ctDNA samples with ALK resistance mutations, which included 4 complex mutations. Two patients with resistance mutations identified by ctDNA analysis responded to brigatinib.

Adverse events (AEs) were similar to what has been previously observed with brigatinib. There was 1 treatment discontinuation due to AEs.

The authors concluded that, although these data are considered preliminary, “the study does reveal activity of brigatinib in this setting, similar to that of lorlatinib, but, potentially, with a more favorable tolerability profile.” They added that the activity of brigatinib should be confirmed in larger trials.

Reference

Stinchcombe TE, Doebele RC, Wang X, Gerber DE, Horn L, Camidge DR. Brief report: Preliminary clinical and molecular analysis results from a single arm phase 2 trial of brigatinib in patients with disease progression after next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors in advanced ALK + non-small cell lung cancer. J Thorac Oncol. Published online October 8, 2020. 2020;S1556-0864(20):30764. doi:10.1016/j.jtho.2020.09.018.