THE FIRST-LINE USE of brigatinib (Alunbrig) was superior to standard-of-care crizotinib (Xalkori) in patients with advanced anaplastic lymphoma kinase (ALK)-positive non–small cell lung cancer (NSCLC), according to the first report of the phase III ALTA-1L trial presented at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer in Toronto.1 Progression-free survival was significantly longer in patients who received the next-generation ALK inhibitor brigatinib. The median progression-free survival was not reached in the brigatinib arm vs 9.8 months in the crizotinib arm. At 1 year, 67% of patients in the brigatinib arm were alive vs 43% of those treated with crizotinib.
D. Ross Camidge, MD
“Brigatinib is a promising new treatment for inhibitor-naive ALK-rearranged NSCLC,” stated lead author D. Ross Camidge, MD, of the University of Colorado Cancer Center, Aurora. “Brigatinib, a next- generation ALK/ ROS1 inhibitor with broad clinical activity, is the only ALK inhibitor to demonstrate activity against multiple EGFR-mutant cell lines, and it has central nervous system penetration. Brigatinib has previously demonstrated the longest post-crizotinib progression-free survival of any ALK inhibitor in NSCLC. So seeing how it performs in the first line in the ALTA-1L trial was very important.”
The study was one of the top five abstracts selected for the Presidential Symposium Plenary Session. These study results were published in The New England Journal of Medicine2 to coincide with Dr. Camidge’s presentation at the meeting.
ALTA-1L WAS a head-to-head open-label, randomized comparison of brigatinib vs crizotinib in patients with advanced ALK-positive NSCLC not previously treated with an ALK inhibitor. The study was conducted at 124 centers in 20 countries, and 275 patients were enrolled. Patients with asymptomatic brain metastasis were included. Up to one previous systemic therapy for advanced NSCLC was allowed.
“Brigatinib has previously demonstrated the longest post-crizotinib progression-free survival of any ALK inhibitor in NSCLC. So seeing how it performs in the first-line in the ALTA-1L trial was very important.”— D. Ross Camidge, MD
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Patients were randomized 1:1 to receive crizotinib vs brigatinib and stratified according to the presence of central nervous system (CNS) disease and prior chemotherapy. Treatment was continued until disease progression or unacceptable toxicity. Crossover from crizotinib to brigatinib was allowed after disease progression in 35 patients.
Treatment arms were well balanced. At baseline, the median age was 59 years, and 55% were female. About 40% were Asian, and 58% were never-smokers. The vast majority of patients (93%) had stage IV disease and adenocarcinoma (96%).
AT THE FIRST interim analysis, the median follow-up was 11 months for brigatinib and 9 months for crizotinib. The study met its primary endpoint of improving progression-free survival. Disease progression or death occurred in 26% of those treated with brigatinib vs 46% of crizotinib-treated patients. The median progression-free survival was not reached with brigatinib vs 9.8 months with crizotinib, representing a 51% reduction in the risk of disease progression or death favoring the next-generation ALK inhibitor (P < .001).
Dr. Camidge said, “Within key subgroups, progression-free survival consistently favored brigatinib. The effect size was greater among those with baseline CNS disease, with an 80% improvement in intracranial progression-free survival for brigatinib.”
Patients without baseline CNS disease had a 28% improvement in progression-free survival with brigatinib. “Progression of CNS disease may be a very early event. The relatively short follow-up is likely to explain why a greater differential effect [between treatments] was seen among those with baseline CNS disease vs those without. Additional follow-up will allow the full differential impact of the two drugs on both early- and late-onset progression events to be assessed,” Dr. Camidge explained.
Preliminary data for overall survival are immature and to date have shown no difference in estimated 1-year survival: 86% with crizotinib vs 85% with brigatinib. However, crossover from the crizotinib arm to brigatinib at disease progression was built into the trial, so little detectable overall survival difference is expected with this design, he said.
Among patients with measurable lesions, the rate of confirmed intracranial response was 78% for brigatinib and 29% for crizotinib (P = .0028). In patients with baseline brain metastases, the intracranial response rate was 67% vs 17% (P < .0001).
The median duration of confirmed response was not reached for brigatinib and 11.1 months for crizotinib. In patients with baseline CNS metastasis, the objective response rate was 78% with brigatinib vs 29% with crizotinib.
Common treatment-emergent adverse events with brigatinib included laboratory abnormalities. Events more commonly reported with crizotinib included gastrointestinal effects, bradycardia, peripheral edema, and visual disturbances. Grades 3 to 5 treatment-emergent adverse events occurred in 61% of the brigatinib arm and 55% of the crizotinib arm. “The majority of dose reductions [for brigatinib] were driven by asymptomatic lab abnormalities,” Dr. Camidge said. ■
DISCLOSURE: ALTA-1L was sponsored by Ariad Pharmaceuticals. Dr. Camidge has received honoraria from Takeda, Genentech/Roche, Novartis, and Pfizer.
1. Camidge R, et al: Brigatinib vs crizotinib in patients with advanced ALK inhibitor-naive advanced ALK+ NSCLC: First report of a phase 3 trial (ALTA-1L). 2018 World Conference on Lung Cancer. Abstract PL02.03. Presented September 25, 2018.
2. Camidge DR, et al: Brigatinib versus crizotinib in ALK-positive non–small-cell lung cancer. N Engl J Med. September 25, 2018 (early release online).
Fiona Blackhall, MD, PhD
FORMAL STUDY discussant, Fiona Blackhall, MD, PhD, of the University of Manchester, UK, welcomed brigatinib (Alunbrig) as a new first-line option for ALK-positive patients but said, “In the absence of comparisons of next-generation ALK inhibitors, it will take some ...!-->!-->