Brigatinib Makes Its Case for ALK-Positive ALCL in Small Study

An anaplastic lymphoma kinase (ALK)-targeted agent induced high response rates for adults with ALK-positive anaplastic large cell lymphoma (ALCL) who had failed on brentuximab vedotin (Adcetris), a small study from France showed.

In 15 patients, treatment with the second-generation ALK inhibitor brigatinib (Alunbrig) yielded a best objective response rate of 93% and a complete response (CR) rate of 73%, reported David Sibon, MD, PhD, of Henri Mondor University Hospital in Créteil, France, and colleagues.

Investigators used brigatinib as a bridge to allogeneic stem-cell transplantation in seven of the responders, and at 2 years, rates of progression-free survival and overall survival (OS) reached 73% and 87%, respectively.

“In comparison with historical controls, the findings of our study support brigatinib as an attractive treatment option in patients with ALK-positive ALCL after the failure of brentuximab vedotin treatment,” Sibon and co-authors concluded in their correspondence to the New England Journal of Medicine.

ALK-positive ALCL is a rare type of T-cell lymphoma that typically occurs in children, adolescents, or young adults, the researchers explained, with the CD30-directed monoclonal antibody brentuximab vedotin used either for patients with newly diagnosed or relapsed/refractory disease.

“Unfortunately, in patients in whom brentuximab vedotin therapy has failed, the outcome is poor,” the study authors said, citing a median OS of 2.9 months and 2-year OS rate of 27% in relapsed/refractory ALCL.

ALK inhibitors are established therapies for ALK-positive non-small cell lung cancer (NSCLC), and the first-generation agent crizotinib (Xalkori) is also approved by the FDA for ALK-positive ALCL in pediatric patients ages 1 year and older and for young adults. But that drug has poor central nervous system (CNS) activity, Sibon’s team noted, and in NSCLC, newer-generation agents have proven superior to crizotinib in the first-line setting and have also shown activity post-crizotinib.

“The few studies that have evaluated ALK inhibitors (mainly crizotinib) in ALK-positive ALCL involved patients who, for the most part, had not previously received brentuximab vedotin therapy, which is not in line with current treatment recommendations in adults,” the researchers wrote.

From 2020 to 2022, the investigators treated 15 adults with ALK-positive ALCL with off-label brigatinib at a dozen centers in the French Lymphoma Study Association. All patients had failed on brentuximab vedotin and were started on the ALK inhibitor at a daily 90-mg dose for 1 week, followed by a daily 180-mg dose.

Participants had a median age of 35 years, 53% were men, and none had CNS involvement. They had received a median of two prior lines of therapy: two-thirds had been treated with brentuximab vedotin for relapsed/refractory disease, while a third received the anti-CD30 drug as first-line therapy. Three patients had a prior autologous stem-cell transplantation, and one had a prior allogeneic stem-cell transplantation.

Of the 15 patients, 14 had a best objective response, per Lugano response criteria, with brigatinib and 11 achieved a CR, with time to CR ranging from 8 to 325 days. Sibon’s group also found a correlation between response and detectable ALK fusion transcripts in the blood.

Four of the patients had previously been treated with the first-generation ALK inhibitor crizotinib (disease resistance in three and sensitivity in one). Of these, brigatinib induced CRs in two patients with crizotinib-resistant disease and the one patient with sensitive disease; the other patient with resistant disease had a partial response with brigatinib.

Three patients needed dose reductions of brigatinib for adverse events (cramps in two patients, dyspnea in another), but none needed to discontinue the drug due to toxicity.

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