Abstract
Results from a phase I/II trial indicate that the investigational ALK inhibitor brigatinib is active in patients with ALK-rearranged non–small cell lung cancer. Patients who had previously received crizotinib—as well as those who hadn't—responded to the drug, which was also active in patients with brain metastases.
Brigatinib (ARIAD Pharmaceuticals), one of the newest next-generation ALK inhibitors under development, shows promising clinical activity in patients with ALK-rearranged non–small cell lung cancer (NSCLC), according to a recent study (Lancet Oncol 2016;17:1683–96).
Approximately 5% of patients with NSCLC have ALK rearrangements. Crizotinib (Xalkori; Pfizer) was the first FDA-approved ALK inhibitor for this subtype, but resistance typically develops, and crizotinib's ability to enter the central nervous system, where metastases often form, is limited. Although two next-generation ALK inhibitors, ceritinib (Zykadia; Novartis) and alectinib (Alecensa; Genentech), have been approved for these patients, they result in only 6 to 9 months of progression-free survival (PFS). In addition, more than 60% of patients receiving ceritinib require reduced doses of the drug due to side effects, which may lessen its effectiveness.
Brigatinib appears to target a broader range of crizotinib-resistance mutations in ALK than do ceritinib and alectinib, says Ross Camidge, MD, of the University of Colorado Cancer Center in Aurora, the study's senior author. It is also active in the central nervous system, he notes.
Camidge and his colleagues evaluated brigatinib's safety and effectiveness in a phase I/II trial. They enrolled a total of 137 patients, 79 of whom had ALK-rearranged NSCLC. Seventy-one of the 79 patients had previously received crizotinib; their confirmed objective response rate to brigatinib was 62%, with a median PFS of 13.2 months. Confirmed objective responses occurred in all eight patients who had never received crizotinib, and their median PFS has not been reached.
“This is the first ALK inhibitor to yield a median progression-free survival of more than one year” after treatment with crizotinib, says Camidge. Brigatinib also demonstrated activity in the central nervous system: Objective responses were seen in five of nine patients with measurable brain metastases who had not received prior radiation therapy.
The study's phase I portion suggested a starting brigatinib dose of 90 mg daily, stepping up to 180 mg after one week. Brigatinib's main side effects included fatigue, nausea, and diarrhea. Some patients did suffer pulmonary side effects, such as dyspnea, within a few days of starting the drug, but they appear to be reduced with the step-up dosing schedule, Camidge notes. “In general, brigatinib is well tolerated and suitable for long-term therapy,” he says.
“The numbers [of patients] in this trial are small enough that it's too early to say brigatinib will be better than any other ALK inhibitor,” says Heather Wakelee, MD, of Stanford University Medical Center in Palo Alto, CA, who wasn't involved with the study. Nonetheless, she says, the results are encouraging. With multiple ALK inhibitors available or undergoing development, the question becomes, “How do we sequence these drugs to give our patients the longest overall survival?”
Trials to help clinicians make these decisions are already under way. A phase III study comparing brigatinib to crizotinib as a first-line treatment for NSCLC started earlier this year. Results from another phase III trial comparing crizotinib to alectinib are anticipated in 2017. –Mitch Leslie
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