Brigatinib Yields Responses in ALK-Rearranged NSCLC

Patients with ALK-rearranged non–small-cell lung cancer (NSCLC) treated with brigatinib showed promising response rates in a phase I/II trial. Responses were seen both in crizotinib-treated and crizotinib-naive patients.

ALK rearrangements occur in approximately 5% of NSCLC patients. “Despite the high initial activity of crizotinib, resistance inevitably develops in most patients,” wrote study authors led by Scott N. Gettinger, MD, of Yale Cancer Center in New Haven, Connecticut. Several other ALK inhibitors have been developed to address this, but brigatinib has a broader spectrum of preclinical activity than ceritinib or alectinib.

This study included a total of 137 patients, 66 of them in a phase I portion and the rest in several phase II cohorts. That full cohort included other advanced malignancies; there were 79 ALK-rearranged NSCLC patients. In the phase II portion of the trial, doses of 180 mg once daily, 90 mg once daily, and 180 mg once daily with a 7-day lead-in at 90 mg were tested. The results were published in Lancet Oncology.

In the phase II portion, all four patients with ALK inhibitor–naive, ALK-rearranged NSCLC achieved an objective response. Of the 42 ALK-rearranged NSCLC patients who had been previously treated with crizotinib, 31 achieved a response (74%). Only 3 of 18 patients with other cancers with abnormalities in brigatinib targets achieved a response (17%), while 5 of 6 patients (83%) of those with ALK-rearranged NSCLC with active, measurable intracranial central nervous system (CNS) metastases and any crizotinib therapy history achieved a response.

In total, 51 of 71 patients with ALK rearrangements and NSCLC with previous crizotinib treatment had an objective response, and 44 were confirmed objective responses (62%). All eight patients in both trial phases who were crizotinib-naive had a confirmed objective response, and there were also three intracranial responses among the six patients with CNS metastases.

The most common treatment-emergent adverse events included nausea in 72 patients (53%), fatigue in 59 patients (43%), and diarrhea in 56 patients (41%). Most of these were grade 1 or 2, and the most common grade 3/4 events included increased lipase concentration (9%), dyspnea (6%), and hypertension (5%). Adverse events required dose reductions in 15% of 98 patients given any of the phase II expansion doses, and 16 patients died during treatment or within 31 days of the last dose of brigatinib (8 due to neoplasm progression).

“Brigatinib shows promising activity in patients with ALK-rearranged NSCLC, including those previously given crizotinib, those who were crizotinib-naive, and those with brain metastases,” the authors concluded.

In an accompanying editorial, Shirish M. Gadgeel, MD, of the Karmanos Cancer Institute at Wayne State University in Detroit, wrote that “further improvements in the outcomes of patients with ALK-positive NSCLC are likely to occur with rational selection of combination therapies on the basis of individual patients’ tumor molecular profiles.” He cautioned, though, that the availability of several ALK inhibitors could cause clinicians to use them in a non-specific sequence. “Not only should the oncology community resist such temptations, but the community should further these advances in a scientifically rigorous manner so that appropriate drugs or drug combinations can be selected for patients with ALK-positive NSCLC.”