Brigatinib Found More Effective for ALK-positive NSCLC Brain Mets Compared With Crizotinib
Brigatinib significantly delayed time to intracranial progression and prolonged PFS compared with crizotinib in patients with ALK+ NSCLC with intracranial metastases.
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The next-generation ALK inhibitor brigatinib substantially delayed time to intracranial progression and prolonged interim progression-free survival (PFS) compared with crizotinib among patients with ALK-positive non-small cell lung cancer (NSCLC) with brain metastases, according to an analysis of the ALTA-1L trial presented at the ESMO 2018 Congress in Munich, Germany.1
Brigatinib met its primary end point in the phase 3 ALTA-1L trial of significantly prolonged PFS (hazard ratio [HR], 0.49; P = .0007) compared with crizotinib during its first interim analysis. This analysis evaluated outcomes of patients who had brain metastases at baseline.
In the phase 3 ALTA-1L trial, 275 patients with stage IIIB/IV ALK-positive NSCLC without prior tyrosine kinase inhibitor (TKI) treatment were randomly assigned to receive brigatinib or crizotinib. The primary end point was PFS — as assessed by a blinded independent review committee (BIRC) — and the secondary end points included intracranial objective response rate (iORR) and intracranial PFS (iPFS).
A brain metastasis of any kind was present at baseline in 33% of patients, and measurable brain metastases were present in 14% of participants. In the study, 14% of patients with any brain metastases received previous treatment with brain radiotherapy.
Brigatinib significantly prolonged iPFS in the intention-to-treat (ITT) and brain metastases cohorts compared with crizotinib. The median iPFS of the ITT population was not reached in both arms, with a 1-year rate of 78% (95% CI, 68%-85%) with brigatinib compared with 61% (95% CI, 50%-71%) with crizotinib (hazard ratio [HR], 0.42; 95% CI, 0.24-0.70; log-rank P = .0006).
Among patients with any baseline brain metastases, the median iPFS was 6 months (95% CI, 4-9 months) with crizotinib and not yet reached with brigatinib. The 1-year iPFS was 67% (95% CI, 47%-80%) with brigatinib compared with 21% (95% CI, 6%-42%) with crizotinib (HR, 0.27; 95% CI, 0.13-0.54; log-rank P < .0001).
Brigatinib significantly prolonged the time to intracranial progression without prior systemic progression by 70% compared with crizotinib in the ITT population (HR, 0.30; 95% CI, 0.15-0.60; P < .001), with a 1-year cumulative incidence of 12% (95% CI, 6%-20%) and 23% (95% CI, 15%-31%), respectively. The brigatinib arm also demonstrated a delayed tie to systemic progression without prior intracranial progression compared with crizotinib (HR, 0.51; 95% CI, 0.30-0.86; P = .017).
The confirmed iORR among patients with any brain metastases at baseline was 67% and 17% with brigatinib or crizotinib, respectively (Cochran-Mantel-Haenszel test P < .0001). The confirmed iORR was higher among patients with measurable brain disease, with a confirmed rate of 78% and 29% with brigatinib or crizotinib, respectively (Cochran-Mantel-Haenszel test P = .0028).
The authors concluded that these data suggest that “brigatinib has superior intracranial activity versus crizotinib in ALK TKI-naive patients with ALK-positive NSCLC.”
Disclosure: This study was funded by Millennium Pharmaceuticals, Inc.
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- Popat S, Janne PA, et al. Intracranial efficacy of brigatinib (BRG) vs crizotinib (CRZ) in the phase 3 ALTA-1L trial. Presented at: the ESMO 2018 Congress; Munich, Germany: October 19-23, 2018. Abstract LBA58.