Good Efficacy of Brigatinib After Failure of 2nd Generation ALK Inhibitors

Targeted Therapy for NSCLC and Development of Resistance

Crizotinib, the first approved tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK), achieved a median progression-free survival (PFS) of 10−11 months in phase III studies when used in 1st-line treatment of metastatic NSCLC. However, resistance to the therapy typically develops within a few months due to secondary mutations in the ALK kinase domain or its further amplification. Progression in the CNS is also common due to poor drug penetration across the blood-brain barrier.

2nd-generation ALK inhibitors, including brigatinib, show higher efficacy against mutations leading to resistance compared to crizotinib and better distribution into the CNS. For this reason, they are often used in 1st-line treatment, although acquired resistance inevitably develops during therapy. Preclinical studies have shown brigatinib's activity against various ALK mutations leading to resistance to crizotinib.

The authors of the presented study focused on the efficacy of brigatinib after the failure of another 2nd-generation ALK inhibitor.

Study Methodology

Twenty patients with advanced ALK-positive NSCLC stage IIIB or IV after progression on at least one 2nd-generation ALK inhibitor participated in the evaluation. Participants had to have a tumor biopsy no older than 60 days before entering the study, and blood was taken for circulating tumor DNA (ctDNA) analysis at the start of treatment. Brigatinib was initially administered at a dose of 90 mg for 7 days, followed by an increase to 180 mg daily. The primary study endpoint was the objective response rate (ORR).

Results

Patients were treated with an average of 3 previous therapeutic regimens, 2 of which were ALK inhibitors: 15 patients had been pretreated with crizotinib, 16 with alectinib, 6 received ceritinib, and 2 were treated with experimental therapies (ensartinib, entrectinib, lorlatinib). At the study entry, 11 patients had CNS metastases.

After an average follow-up of 22 months, the median PFS was 7.0 months (95% confidence interval [CI] 4.6−10.1). ORR was 40% (95% CI 19−62) with an average duration of response of 5.3 months (95% CI 3.6 to not evaluable). The safety profile was consistent with previous observations.

Analysis of Resistance-Associated Mutations

Next-generation sequencing was successfully performed on 10 tumor tissue samples, with resistance-associated mutations detected in 6 samples. An objective response to brigatinib treatment was observed in 3 patients with these mutations.

ctDNA analysis was successful in 13 samples, with mutations detected in 7 cases, 4 of which were categorized as complex. An objective response to treatment was achieved in 2 patients with mutations detected by ctDNA analysis.

Conclusion

Despite the small number of patients in this preliminary study, brigatinib appears to show efficacy comparable to lorlatinib after the failure of 2nd-generation ALK inhibitors, with a better safety profile. These findings need to be confirmed in larger clinical trials.

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Source: Stinchcombe T. E., Doebele R. C., Wang X., et al. Preliminary clinical and molecular analysis results from a single-arm phase 2 trial of brigatinib in patients with disease progression after next-generation ALK tyrosine kinase inhibitors in advanced ALK+ NSCLC. J Thorac Oncol 2021; 16 (1): 156−161, doi: 10.1016/j.jtho.2020.09.018.