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J Clin Oncol. 2017 Aug 1;35(22):2490-2498. doi: 10.1200/JCO.2016.71.5904. Epub 2017 May 5.

Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial.

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Dong-Wan Kim, Seoul National University Hospital; Myung-Ju Ahn, Samsung Medical Center; Sang-We Kim, Asan Medical Center, Seoul, South Korea; Marcello Tiseo, University Hospital of Parma, Parma, Italy; Karen L. Reckamp, City of Hope, Duarte, CA; Karin Holmskov Hansen, Odense University Hospital, Odense, Denmark; Rudolf M. Huber, University Hospital of Munich, German Centre for Lung Research, Munich, Germany; Howard L. West, Swedish Cancer Institute, Seattle, WA; Harry J.M. Groen, University of Groningen, University Medical Center Groningen, Groningen; Egbert F. Smit, VU University Medical Center, Amsterdam, the Netherlands; Maximilian J. Hochmair, Otto Wagner Hospital, Vienna, Austria; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Scott N. Gettinger, Yale Cancer Center, New Haven, CT; Corey J. Langer, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA; Luis G. Paz-Ares Rodríguez, Hospital Universitario 12 de Octubre, Madrid, Spain; Edward S. Kim, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC; William Reichmann, Frank G. Haluska, and David Kerstein, ARIAD Pharmaceuticals, Cambridge, MA; and D. Ross Camidge, University of Colorado Cancer Center, Aurora, CO.


Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell 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 progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

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