Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: A randomized, multicenter phase II trial

Dong Wan Kim*, Marcello Tiseo, Myung Ju Ahn, Karen L. Reckamp, Karin Holmskov Hansen, Sang We Kim, Rudolf M. Huber, Howard L. West, Harry J.M. Groen, Maximilian J. Hochmair, Natasha B. Leighl, Scott N. Gettinger, Corey J. Langer, Luis G.Paz Ares Rodríguez, Egbert F. Smit, Edward S. Kim, William Reichmann, Frank G. Haluska, David Kerstein, D. Ross Camidge

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: Most crizotinib-treated patients with anaplastic lymphoma kinase gene (ALK)-rearranged non-smallcell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods: Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results: Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion: Brigatinib yielded substantial whole-body and intracranial responses as well as robust progressionfree survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

Original languageEnglish
Pages (from-to)2490-2498
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number22
DOIs
Publication statusPublished - 1 Aug 2017

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