Recent advances in molecular profiling in non–small-cell lung cancer (NSCLC) have resulted in the development of molecularly targeted therapies based on individual genetic or protein profiles. Among patients with NSCLC, approximately 5% harbor chromosomal rearrangements of a gene called anaplastic lymphoma kinase (ALK).
The ALK gene rearrangement produces an abnormal ALK protein that causes the cells to grow and spread. Retrospective analysis of data from multiple clinical trials show that ALK rearrangement is a negative prognostic factor in NSCLC.1 Since 2011, the FDA has approved 4 agents that inhibit the activity of the abnormal ALK protein: crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig).
On April 28, 2017, the FDA granted accelerated approval to brigatinib for the treatment of patients with ALK-positive metastatic NSCLC who have progressed while using or are intolerant to crizotinib. This approval was based on preliminary data from the phase 2 ALTA trial, which enrolled 222 patients with locally advanced or metastatic ALK-positive NSCLC whose disease progressed while using crizotinib. Patients received either 90 mg of brigatinib once daily (n = 112; arm A) or 180 mg once daily following a 7-day lead-in of 90 mg once daily (n = 110; arm B).2,3
Initial analysis of data from the ALTA trial showed objective tumor responses in approximately 50% of the patients in both study arms. The median duration of tumor response was approximately 14 months.2
In October 2017, updated findings from the ALTA trial were presented at the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer. After a median follow-up of 16.8 months and 18.6 months in arms A and B, respectively, 32% of patients in arm A (90 mg) and 41% of patients in arm B (180 mg) continued to receive brigatinib. The Independent Review Committee (IRC) confirmed objective response rates of 51% in arm A and 55% in arm B. IRC-assessed median duration of response was 13.8 months and 14.8 months, respectively.3
Secondary end points included IRC-assessed median progression-free survival (PFS) and overall survival (OS). Median PFS rates were 9.2 months and 16.7 months, in arms A and B, respectively. Median OS was not reached in arm A and was 27.6 months in arm B.3
Among patients in the ALTA trial with measurable brain metastases at baseline (n = 26, arm A; n = 18, arm B), 50% and 67% achieved an IRC-confirmed intracranial objective response, respectively. The median duration of intracranial response was not reached in arm A and was 16.6 months in arm B. In patients with any brain metastases at baseline, the median intracranial PFS was 12.8 months in arm A and 18.4 months in arm B.3
The most common grade ≥3 brigatinib-related adverse events (AEs) in arm A and arm B, respectively, included increased blood creatine phosphokinase (3% vs 11%), hypertension (4% vs 4%), increased lipase (4% vs 4%), pneumonitis (2% vs 4%), and rash (1% vs 4%). Dose reductions attributed to AEs were reported in 9% of patients in arm A and 30% of patients in arm B, and treatment discontinuations due to AEs were required in 4% and 11% of patients, respectively. Researchers concluded that the efficacy and safety data from the updated ALTA trial analysis continue to support future trials with the 180-mg dosing regimen.3
Commenting on these data, Myung-Ju Ahn, MD, Professor, Department of Hematology & Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, said in a press release, “The updated data from the ALTA trial further support the clinical benefit of brigatinib. I am especially encouraged by the efficacy seen in patients with brain metastases.”3
1. Kulig K, Wang Y, Iyer S, et al. Predictive and prognostic value of ALK gene rearrangement in non-small cell lung cancer. Epidemiology. 2014;4:146.
2. Takeda. Takeda Announces FDA Accelerated Approval of ALUNBRIGTM (brigatinib). www.takeda.com/newsroom/newsreleases/2017/alunbrig-fda-approval/. Accessed January 25, 2018.
3. ASCO Post. IASLC 2017: Brigatinib in ALK-positive non–small cell lung cancer. October 16, 2017. www.ascopost.com/News/58146. Accessed January 25, 2018.