Brigatinib vs. Crizotinib in the Treatment of ALK-Positive NSCLC – Results of the Second Interim Analysis of the ALTA-1L Study
The anaplastic lymphoma kinase inhibitor brigatinib demonstrated superiority over crizotinib in the first interim analysis of the ALTA-1L study in terms of progression-free survival and improvement in health-related quality of life in patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene rearrangement. The second interim analysis results published in 2020 confirm these primary findings.
Introduction
ALK gene rearrangement is observed in 3–5% of NSCLC cases. The discovery of this gene rearrangement has led to improved patient prognosis through the administration of ALK inhibitors, including brigatinib and crizotinib.
However, when administering crizotinib, which is a first-generation ALK inhibitor, disease progression in the CNS has been observed due to poor drug penetration across the blood-brain barrier or extracranial progression due to the emergence of secondary ALK mutations or the activation of secondary signaling pathways.
For patients refractory to crizotinib therapy, the administration of brigatinib in phase I/II clinical trials led to high systemic and CNS therapeutic responses as well as an improvement in median progression-free survival (PFS). Brigatinib is an ALK inhibitor with broad activity against ALK gene mutations causing resistance.
The superiority of brigatinib over crizotinib was also demonstrated in the first interim analysis of the ALTA-1 (phase III) clinical study in patients with advanced ALK-positive NSCLC who had not previously been treated with an ALK inhibitor. In 2020, the interim results of the second analysis were published, confirming the superiority of brigatinib over crizotinib.
Study Progress and Results
Patients were randomized 1:1 to therapy with brigatinib at a dose of 180 mg once daily (7-day introductory dose of 90 mg once daily) or crizotinib at a dose of 250 mg twice daily. The primary goal of the study was to evaluate PFS by a blinded independent review committee. Other goals included evaluation of efficacy by investigators, pharmacokinetic parameters, and patient treatment assessments.
A total of 275 patients participated in the study, with 137 assigned to brigatinib therapy and 138 to crizotinib therapy. The median duration of treatment was 24.3 months for patients treated with brigatinib and 8.4 months for patients taking crizotinib. Brigatinib therapy demonstrated consistent superiority in the PFS parameter evaluated by the independent review committee compared to crizotinib (median PFS 24.0 vs. 11.0 months; hazard ratio [HR] 0.49; 95% CI 0.35–0.68; p < 0.0001). Similarly, PFS evaluated by investigators showed a median of 29.4 vs. 9.2 months; HR 0.43; 95% CI 0.31–0.61.
Brigatinib therapy compared to crizotinib also showed a longer time to deterioration in overall health status/quality of life score (HR 0.70; 95% CI 0.49–1.00; p = 0.049). The daily area under the curve of plasma concentration over time was not a predictor of PFS with brigatinib administration (HR 1.005; 95% CI 0.98–1.031; p = 0.69).
No new safety risks were observed with brigatinib therapy during the study.
Conclusion
The results of the second interim analysis confirm the superiority of brigatinib over crizotinib in the treatment of advanced ALK-positive NSCLC in patients previously untreated with other ALK inhibitors.
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Source: Camidge D. R., Kim H. R., Ahn M. J. et al. Brigatinib versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. J Clin Oncol 2020 Nov 1; 38 (31): 3592–3603, doi: 10.1200/JCO.20.00505.
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