Medline ® Abstract for Reference 81
of 'Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents'
Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial.
Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, Huber RM, West HL, Groen HJM, Hochmair MJ, Leighl NB, Gettinger SN, Langer CJ, Paz-Ares Rodríguez LG, Smit EF, Kim ES, Reichmann W, Haluska FG, Kerstein D, Camidge DR
J Clin Oncol. 2017;35(22):2490. Epub 2017 May 5.
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.
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; Edwar