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New ALK Inhibitor, Brigatinib, Active in ALK-Rearranged Non–Small Cell Lung Cancer

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Key Points

  • Brigatinib was active in patients with ALK-rearranged NSCLC with and without prior crizotinib treatment.
  • A randomized phase II trial is assessing two dosage regimens.

In a phase I/II study reported in The Lancet Oncology, Gettinger et al found that the anaplastic lymphoma kinase (ALK) inhibitor brigatinib, which showed preclinical activity against ALK mutants resistant to crizotinib (Xalkori) and other ALK inhibitors, was active in patients with ALK-rearranged non–small cell lung cancer (NSCLC) with or without prior crizotinib treatment.

In the open-label study, including patients from 9 sites in the United States and Spain, the phase II doses consisted of 180 mg once daily (dose selected from phase I portion) as well as 90 mg once daily and 180 mg once daily with a 7-day lead-in at 90 mg.

Response Rates

Objective response was achieved in 4 of 4 patients (100%) with ALK inhibitor–naive ALK-rearranged NSCLC; 31 of 42 patients (74%) with crizotinib-treated ALK-rearranged NSCLC; 0 of 1 patient with epidermal growth factor receptor (EGFR) T790M–positive NSCLC and resistance to 1 previous EGFR tyrosine kinase inhibitor; 3 of 18 patients (17%) with other cancers with abnormalities in brigatinib targets; and 5 of 6 patients (83%) with crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active measurable intracranial central nervous system metastases, including intracranial response in 3 (50%). Overall, 51 of 71 patients (72%) with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response, with 44 (62%) having a confirmed objective response. Confirmed objective response was observed in 8 of 8 (100%) crizotinib-naive patients with ALK-rearranged NSCLC.

Adverse Events

The most common grade 3 or 4 adverse events across all doses were increased lipase (9%), dyspnea (6%), and hypertension (5%). Serious adverse events occurring in ≥ 5% of patients were dyspnea (7%), pneumonia (7%), and hypoxia (5%).

The investigators concluded: “Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg).”

The study was funded by ARIAD Pharmaceuticals.

Scott N. Gettinger, MD, of Yale School of Medicine, Yale Cancer Center, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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