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Camidge, D. Ross; Kim, Dong-Wan; Tiseo, Marcello; Langer, Corey J.; Ahn, Myung-Ju; Shaw, Alice T.; Huber, Rudolf M.; Hochmair, Maximilian J.; Lee, Dae Ho; Bazhenova, Lyudmila A.; Gold, Kathryn A.; Ou, Sai-Hong Ignatius; West, Howard L.; Reichmann, William; Haney, Jeff; Clackson, Tim; Kerstein, David and Gettinger, Scott N. (2018): Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials. In: Journal of Clinical Oncology, Vol. 36, No. 26: pp. 2693-2701

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PurposeIn patients with crizotinib-treated, anaplastic lymphoma kinase gene (ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases.Patients and Methods: Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II;ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113;ClinicalTrials.gov identifier: NCT02094573;patients in arm A received 90 mg once daily;patients in arm B received 180 mg once daily with 7-day lead-in at 90 mg). Primary end points (systemic objective response rates [ORRs]) were previously reported. Independent review committees assessed intracranial efficacy in patients with baseline brain metastases.Results: Most patients with ALK-positive NSCLC had baseline brain metastases (50 of 79 [63%], phI/II;80 of 112 [71%] and 73 of 110 [66%] in ALTA arms A and B, respectively), many of whom had no prior brain radiotherapy (23 of 50 [46%], phI/II;32 of 80 [40%], ALTA arm A;30 of 73 [41%], arm B). All patients, except four in phI/II, had received crizotinib. Among patients with measurable ( 10 mm) brain metastases, confirmed intracranial ORR was 53% (eight of 15;95% CI, 27% to 79%) in phI/II, 46% (12 of 26;95% CI, 27% to 67%) in ALTA arm A, and 67% (12 of 18;95% CI, 41% to 87%) in arm B. Intracranial ORRs were similar in subsets without prior radiation or progression postradiation. Among patients with any baseline brain metastases, median intracranial progression-free survival (iPFS) was 14.6 months (95% CI, 12.7 to 36.8 months), phI/II;15.6 months (95% CI, 9.0 to 18.3 months), ALTA arm A;18.4 months (95% CI, 12.8 months to not reached), ALTA arm B.Conclusion: Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in).

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