Novel ALK Inhibitor Shows Activity in Advanced NSCLC

Poorly differentiated squamous cell carcinoma; source: Ed Uthman, Wikimedia Commons

The new ALK inhibitor ceritinib showed strong antitumor activity in a phase I expansion study of patients with advanced non-small-cell lung cancer (NSCLC).

Patients with ALK-rearranged lung tumors have previously seen good results with the ALK inhibitor crizotinib, but resistance eventually develops and the majority of patients suffer a relapse within 12 months on crizotinib. “Treatment options after the failure of crizotinib are limited and include cytotoxic chemotherapy, palliative radiotherapy, or supportive care,” wrote study authors led by Alice T. Shaw, MD, PhD, of Massachusetts General Hospital in Boston. Shaw and colleagues conducted a phase I study of the novel ALK inhibitor ceritinib; the drug is 20 times as potent as crizotinib in enzymatic assays. The results were published in the March 27 issue of the New England Journal of Medicine.

The study included 59 patients in a dose-escalation phase, followed by an additional 71 patients in an expansion phase using the maximum tolerated dose established in the first part of the trial. That dose was determined to be 750 mg daily; dose-limiting events included diarrhea, vomiting, dehydration, hypophosphatemia, and elevated alanine aminotransferase level.

A total of 114 NSCLC patients received at least 400 mg ceritinib per day, and among those patients the overall response rate was 58%. Eighty patients had received crizotinib prior to entering this trial, and the response rate among those patients was 56%. The responses were observed in patients with ALK mutations known to promote resistance as well as in those with no observable mutations. Among the 114 patients at 400 mg per day or greater, the median progression-free survival was 7 months.

In an accompanying editorial, Roman K. Thomas, MD, of the University of Cologne in Germany, wrote that it remains to be seen whether ceritinib would be better suited as a front-line therapy in certain patients, or as a secondary treatment following the failure of crizotinib. “It is plausible that the progression-free survival of these two lines of therapy may simply be added to ultimately confer a prolongation of overall survival,” he wrote. However, the new study’s finding that those who had not previously received crizotinib had about 3 months longer PFS potentially “supports such a front-line treatment scenario.” Of course, if ceritinib resistance cannot be overcome by other drugs that would limit the drug’s front-line efficacy.

The study authors called for confirmatory trials of ceritinib’s activity, and Thomas concluded that these results are “good news for patients with ALK-rearranged lung cancer.”