Brigatinib is tolerable and has antitumor activity in crizotinib-resistant ALK-positive NSCLC.

  • Major finding: Brigatinib is tolerable and has antitumor activity in crizotinib-resistant ALK-positive NSCLC.

  • Clinical relevance: Brigatinib achieves whole-body and intracranial responses as well as robust progression-free survival.

  • Impact: Brigatinib may be effective in patients with crizotinib-resistant ALK-positive NSCLC.

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The ALK inhibitor crizotinib achieves initial responses in patients with metastatic ALK-positive non–small cell lung cancer (NSCLC), but most patients acquire crizotinib resistance. These patients can be treated with second-generation ALK inhibitors, but ALK kinase domain mutations lead to resistance. The investigational next-generation ALK tyrosine kinase inhibitor brigatinib has broad activity against a range of ALK resistance mutations and has demonstrated antitumor activity in an ongoing phase I/II trial. At a dose of 180 mg daily, brigatinib led to moderate or severe pulmonary adverse events in some patients, the frequency of which were reduced at a dose of 90 mg per day, or 180 mg per day with a 7-day lead-in at 90 mg. Based on these findings, Kim and colleagues assessed brigatinib safety and efficacy in an open-label phase II trial of 222 patients with crizotinib-refractory advanced ALK-positive NSCLC. In arm A, 109 patients were treated with 90 mg brigatinib once daily, and in arm B 154 patients received 180 mg once daily with a 7-day lead-in at 90 mg. The primary end point was overall response rate, and secondary end points included central nervous system response, duration of response, progression-free survival, and safety. Brigatinib exhibited an acceptable safety profile. The overall response rate was 45% in arm A, including 1 complete response, and 54% in arm B, including 4 complete responses, with a median duration of response 13.8 months in both arms. The median progression-free survival was 9.2 months in arm A and 12.9 months in arm B. The intracranial overall response rate was 42% (11 of 26 patients) and 67% (12 of 18 patients) in evaluable patients with brain metastases in arms A and B respectively. Collectively, these findings indicate that brigatinib is safe in patients with crizotinib-resistant ALK-positive NSCLC and exhibits whole-body and intracranial activity, supporting further clinical investigation of brigatinib at the 180 mg dose (with lead-in).

Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol 2017 May 5 [Epub ahead of print].