Brigatinib versus Crizotinib in ALK-Positive Non–Small-Cell Lung Cancer

Abstract

BACKGROUNDBrigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear. METHODSIn an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred. RESULTSA total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median followup was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. CONCLUSIONSAmong patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501.

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“…In phase I/II trials in crizotinib resistance ALK‐positive NSCLC patients, brigatinib showed 72% overall response with a median PFS of 11–13 months . A recently published phase III trial showed a superior efficacy of brigatinib as compared with crizotinib in the treatment‐naïve ALK‐fusion positive NSCLC, with an estimated 12‐month event‐free survival of 67% . The predominant resistance mutation seen in response to alectinib therapy is ALK‐G1202R which is resistant to most ALK TKIs, with the exception of lorlatinib (see below).…”

Clinical Feature and Survival Outcomes of Lung Cancer with ALK Mutation Positive and Treated with Crizotinib, Single Centre Experience

“…Birinci basamakta alektinib, brigatinib ve ceritinib, crizotinib veya kemoterapiye göre üstünlüğü gösterilmiş diğer ajanlardır. (9)(10)(11). Crizotinib altında progresyon gösteren hastalarda ise benzer şekilde alektinib, ceritinib, brigatinib ve lorlatinib kemoterapiye karşı etkinlikleri gösterilmiş ajanlardır.…”

Effects of Strong CYP2C8 or CYP3A Inhibition and CYP3A Induction on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

“…1 More recently, a phase 3 trial in crizotinib-naive patients with ALK-positive NSCLC showed that progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib (12-month progression-free survival, 67% versus 43%; hazard ratio, 0.49 [95%CI, 0.33-0.74]; P < .001). 2 The recommended dose of brigatinib is 90 mg orally once daily for the first 7 days of treatment, which, if tolerated, is followed by escalation to 180 mg once daily. Brigatinib single-and repeat-dose systemic exposures increased dose-proportionally following administration in patients with cancer across the dose range of 60-240 mg once daily.…”