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Brigatinib shows promise for crizotinib-refractory ALK+ NSCLC

Pearl Toh
22 Jun 2017

The next-generation ALK inhibitor brigatinib yielded high and durable responses in both whole-body and intracranial endpoints, with a median progression-free survival (PFS) of over 1 year in patients with ALK-positive non-small cell lung cancer (NSCLC) whose disease had progressed after crizotinib, according to the ALTA* trial.

“Brigatinib has a broader spectrum of coverage of resistance mechanisms than many of [the] other next-generation drugs, especially at the higher dose. So the broader your spectrum of coverage of resistance mechanisms, the longer you control the disease,” said principal investigator Dr D. Ross Camidge, director of Thoracic Oncology at the University of Colorado School of Medicine in Aurora, Colorado, US.

Although other second-generation ALK inhibitors in the postcrizotinib setting such as alectinib and ceritinib also showed similarly high response rates, secondary mutations including G1202R, which confers resistance to therapy, have been identified in these patients whose disease had progressed. Brigatinib was shown to inhibit all ALK resistance mutations tested in preclinical studies, including the G1202R mutation. [Clin Cancer Res 2016;22:5527-5538]

The ongoing open-label multinational phase II study enrolled 222 patients with locally advanced or metastatic ALK-positive NSCLC who had disease progression while receiving crizotinib. The patients were randomized 1:1 to oral brigatinib 90 mg (arm A) or 180 mg with a 7-day lead-in at 90 mg (arm B), once daily for both arms. [J Clin Oncol 2017;doi:10.1200/JCO.2016.71.5904]

After a median follow-up of 8 months, objective response rates (ORRs) were 48 percent in patients in arm A and 53 percent in arm B, as assessed by an independent review committee. The duration of response was similar in both arms, at a median of 13.8 months. The median PFS was 9.2 and 15.6 months in arms A and B, respectively.    

Among the 44 patients with measurable brain metastases (≥10 mm) at baseline based on MRI, the intracranial ORR was 42 percent (95 percent confidence interval [CI], 23–63) in arm A and 67 percent (95 percent CI, 12–18) in arm B. The median duration of intracranial response has yet to be reached among patients with intracranial response in both arms.  

“What brigatinib at this higher dose shows is comparable response rates to other next-generation ALK inhibitors postcrizotinib but ─ and this is important ─ the duration of this benefit appears to be significantly longer,” said Camidge.

“[A]ny differences among [the next-generation] drugs in their ability to suppress clinically relevant ALK mutations, including those that may not be dominant initially but could emerge later, are more likely to be reflected in PFS or duration of response,” explained Camidge and co-authors.

The most common treatment-emergent AEs of any grade included nausea, diarrhoea, headache, and cough.

While the 180 mg dose had been associated with early-onset moderate/severe pulmonary adverse events (AEs) in a small proportion of patients in a previous phase II expansion trial, [Ann Oncol 2016;27:vi419-vi420] no such AEs occurred after escalation to 180 mg in the current study, with all the 14 events (6 percent) reported occurring at 90 mg (in arm A or during the lead-in period in arm B).

“A lead-in dose of 90 mg once daily for 1 week before escalation to 180 mg once daily seemed to reduce the risk of these AEs compared with starting at 180 mg once daily,” observed Camidge and co-authors.

“Patients treated with brigatinib should be monitored for new or worsening respiratory symptoms, particularly during the first week of treatment. Management of early pulmonary AEs should include dose interruption and prompt clinical evaluation,” they added. 

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