The FDA has approved the ALK inhibitor brigatinib for patients with metastatic non-small cell lung cancer who cannot take crizotinib or whose disease worsened despite its use. The decision was based upon results of a phase II study that assessed two drug doses, with overall response rates of 45% and 56% respectively. The drug's effect on overall survival remains unclear, as does the optimal sequence of brigatinib and the three other ALK inhibitors.

With the FDA's recent approval of brigatinib (Alunbrig; Takeda Pharmaceutical), clinicians now have four ALK inhibitors to treat patients with non–small cell lung cancer (NSCLC). However, the order in which they should be prescribed to provide the most benefit to patients isn't clear.

In 2011, crizotinib (Xalkori; Pfizer) became the first targeted therapy approved for the 3% to 7% of patients with locally advanced or metastatic NSCLC who carry mutations in ALK. However, resistance to crizotinib typically develops within a year, often due to further ALK mutations. Two other drugs that target some of these mutations garnered FDA approval in 2014: ceritinib (Zykadia; Novartis) and alectinib (Alecensa; Genentech). The agency cleared them for use in patients with metastatic, ALK-positive NSCLC who can't take crizotinib or whose tumors have progressed after treatment with the drug.

Now, the FDA has granted accelerated approval to brigatinib for this same group of patients. In the phase II ALTA trial that spurred the decision, researchers randomly assigned 222 crizotinib-refractory patients to either of two groups. One group received 90 mg of brigatinib daily. The other started with a dose of 90 mg per day, which increased to 180 mg after the first week. After a median follow-up of 8 months, the overall response rate was 45% in the 90-mg group and 56% in the 180-mg group. The study also showed positive effects in the 44 patients with measurable brain metastases, which shrank in 42% of individuals who received 90 mg of brigatinib and in 67% of patients treated with the higher dose.

Although the trial didn't assess overall survival, progression-free survival was 9.2 months in the 90-mg group and 12.9 months in the 180-mg group. Diarrhea, nausea, and headache were the most common side effects of brigatinib, with 6% percent of patients developing pulmonary adverse events such as dyspnea, hypoxia, and pneumonia.

Brigatinib's approval creates a quandary. “The good news is we have several effective drugs,” says Scott Gettinger, MD, of Yale Medical School in New Haven, CT, who took part in the ALTA trial. “The problem is that we don't know how to best sequence them.”

Which drug patients should receive for first-line treatment is unclear, for instance. Crizotinib is the only ALK inhibitor approved for that use, but alectinib may soon join it, researchers say. The recently reported phase III J-ALEX trial in Japan suggested that alectinib outperforms crizotinib, as gauged by progression-free survival, and causes less severe side effects. If the results of the global phase III ALEX trial, which is also comparing alectinib to crizotinib as a first-line treatment, favor alectinib as well, “a lot of people will switch,” says Paul Bunn, MD, of the University of Colorado Denver School of Medicine.

As for brigatinib, the ALTA-1L study is pitting it against crizotinib as a first-line treatment. Given the uncertainties of intertrial comparisons, Bunn says, “to get into the first line, brigatinib has to be way better than crizotinib, compared to the improvement of alectinib over crizotinib.” Further research may eventually allow clinicians to make the best choices, Gettinger says, but “we are going to struggle with this question for some time.” –Mitch Leslie