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

被引:422
作者
Kim, Dong-Wan [1 ]
Tiseo, Marcello [4 ]
Ahn, Myung-Ju [2 ]
Reckamp, Karen L. [5 ]
Hansen, Karin Holmskov [6 ]
Kim, Sang-We [3 ]
Huber, Rudolf M. [7 ]
West, Howard L. [8 ]
Groen, Harry J. M. [9 ]
Hochmair, Maximilian J. [11 ]
Leighl, Natasha B. [12 ]
Gettinger, Scott N. [13 ]
Langer, Corey J. [14 ]
Rodriguez, Luis G. Paz-Ares [15 ]
Smit, Egbert F. [10 ]
Kim, Edward S. [16 ]
Reichmann, William [17 ]
Haluska, Frank G. [17 ]
Kerstein, David [17 ]
Camidge, D. Ross [18 ]
机构
[1] Seoul Natl Univ Hosp, Seoul, South Korea
[2] Samsung Med Ctr, Seoul, South Korea
[3] Asan Med Ctr, Seoul, South Korea
[4] Univ Hosp Parma, Parma, Italy
[5] City Hope Natl Med Ctr, Duarte, CA USA
[6] Odense Univ Hosp, Odense, Denmark
[7] Univ Hosp Munich, German Ctr Lung Res, Munich, Germany
[8] Swedish Canc Inst, Seattle, WA USA
[9] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands
[10] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands
[11] Otto Wagner Hosp, Vienna, Austria
[12] Princess Margaret Canc Ctr, Toronto, ON, Canada
[13] Yale Canc Ctr, New Haven, CT USA
[14] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA
[15] Hosp Univ 12 Octubre, Madrid, Spain
[16] Levine Canc Inst, Carolinas HealthCare Syst, Charlotte, NC USA
[17] ARIAD Pharmaceut, Cambridge, MA USA
[18] Univ Colorado, Ctr Canc, Aurora, CO USA
关键词
BRAIN METASTASES; OPEN-LABEL; SAFETY; RESISTANCE; INHIBITOR; CERITINIB; CHEMOTHERAPY; ASCEND-1; AP26113; POTENT;
D O I
10.1200/JCO.2016.71.5904
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2017 by American Society of Clinical Oncology
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页码:2490 / +
页数:11
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