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

Abstract

BACKGROUND:

Brigatinib, 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.

METHODS:

In 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.

RESULTS:

A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up 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.

CONCLUSIONS:

Among 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 .).

• Authors: D Ross Camidge, Hye Ryun Kim, Myung-Ju Ahn, James Chih-Hsin Yang, Ji-Youn Han, Jong-Seok Lee, Maximilian J Hochmair, Jacky Yu-Chung Li, Gee-Chen Chang, Ki Hyeong Lee, Cesare Gridelli, Angelo Delmonte, Rosario Garcia Campelo, Dong-Wan Kim, Alessandra Bearz, Frank Griesinger, Alessandro Morabito, Enriqueta Felip, Raffaele Califano, Sharmistha Ghosh, Alexander Spira, Scott N Gettinger, Marcello Tiseo, Neeraj Gupta, Jeff Haney, David Kerstein, Sanjay Popat
• Journal: The New England journal of medicine (N Engl J Med) Vol. 379 Issue 21 Pg. 2027-2039 (11 22 2018) ISSN: 1533-4406 [Electronic] United States
• PMID: 30280657 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organophosphorus Compounds
• Pyrimidines
• Crizotinib
• ALK protein, human
• Anaplastic Lymphoma Kinase
• brigatinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Anaplastic Lymphoma Kinase (analysis, antagonists & inhibitors)
• Antineoplastic Agents (adverse effects, therapeutic use)
• Brain Neoplasms (secondary)
• Carcinoma, Non-Small-Cell Lung (chemistry, drug therapy, secondary)
• Crizotinib (adverse effects, therapeutic use)
• Female
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (chemistry, drug therapy, pathology)
• Male
• Middle Aged
• Organophosphorus Compounds (adverse effects, therapeutic use)
• Progression-Free Survival
• Pyrimidines (adverse effects, therapeutic use)