Abstract
The next-generation ALK inhibitor alectinib overcomes acquired crizotinib resistance in NSCLC.
Major finding: The next-generation ALK inhibitor alectinib overcomes acquired crizotinib resistance in NSCLC.
Concept: Alectinib crosses the blood–brain barrier and leads to objective responses in patients with CNS metastases.
Impact: Alectinib may be effective in refractory ALK-rearranged NSCLC and benefit patients with CNS involvement.
Treatment with the FDA-approved ALK inhibitor crizotinib leads to objective responses in approximately 60% of patients with ALK-rearranged non–small cell lung cancer (NSCLC), but acquired resistance develops in the vast majority of patients. The central nervous system (CNS) is a particularly common site of progressive disease in crizotinib-treated patients, suggesting that ALK inhibitors that not only can overcome acquired crizotinib resistance but also penetrate the blood–brain barrier are needed. Gadgeel, Gandhi, and colleagues evaluated the next-generation ALK inhibitor alectinib in 47 patients with crizotinib-resistant ALK-rearranged NSCLC, including patients with asymptomatic CNS metastases, in a single-arm, open-label, multicenter phase 1/2 study. The primary objective was to determine the recommended phase 2 dose, and secondary objectives included evaluation of safety, activity, and pharmacokinetics. In a report on the dose-finding part of the study, the authors showed that alectinib was well tolerated at all dose levels, with the most common adverse events being low-grade fatigue, myalgia, and peripheral edema, and noted that alectinib had favorable pharmacokinetics. Of 44 evaluable patients, 24 (55%) had an objective response, including one complete response, and 16 (36%) had stable disease. Encouragingly, among the 21 patients with CNS metastases at baseline, 6 (29%) had a complete CNS response, 5 (24%) had a partial CNS response (including one patient with leptomeningeal carcinomatosis), and 8 (38%) had CNS disease stabilization. Consistent with these findings suggesting that alectinib effectively penetrates the blood–brain barrier, measureable levels of alectinib were found in the cerebrospinal fluid (CSF) of 5 of 5 patients with CNS metastases analyzed, with a linear relationship between CSF and plasma alectinib levels. These initial findings suggest that alectinib has promising antitumor activity and can penetrate the CNS in patients with crizotinib-resistant ALK-rearranged NSCLC.
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