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.

Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15:1119–28.

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