The US Food and Drug Administration (FDA) today granted accelerated approval to Alectinib (Alecensa) for the treatment of patients with ALK (Anaplastic Lymphoma Kinase)-rearranged metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib (Xalkori).
ALK-rearrangement positive NSCLC accounts for 5% of all non-small cell lung cancer diagnoses, and typically occurs in younger patients with a history of light or no smoking. Most ALK+ patients respond to first line therapy with crizotinib (Xalkori). Unfortunately, treatment resistance develops in most patients with the disease recurring and progressing. Most of these patients whose disease progresses present with metastases in the central nervous system (brain), an area where crizotinib is known to have poor penetrance.
Mechanism of Action: Alectinib is a targeted therapeutic- a potent and selective ALK inhibitor that was designed to have a greater inhibitory activity against ALK compared to crizotinib. Alectinib effectively crosses the blood-brain barrier, and is therefore active against brain metastases that are frequently seen in crizotinib-resistant ALK+ patients. Preclinical studies have demonstrated that alectinib inhibits certain mutations in ALK, such as L1196M, C1156Y and F1174L that confer resistance to crizotinib, suggesting that this medication may be effective in patients who become resistant to crizotinib through these specific mechanisms.
Alectinib is marketed by Genentech, and was cleared for sale in Japan in July, 2014.
Alectinib is the second such targeted therapeutic to be approved for the second line treatment of ALK+ NSCLC patients in the United States, the first being ceritinib (Zykadia) approved for this indication in April, 2014. Several other compounds are currently under development for the treatment of ALK rearrangement positive non-small cell lung cancer patients.
Clinical Trial Results: Alectinib was approved by the FDA under its accelerated approval program, which allows for the quicker (conditional) approval of medications for serious or life-threatening illnesses that fill an unmet medical need. Accelerated approval by the FDA is based on evidence that medications such as Alectinib have effects reasonably likely to predict clinical benefit. The FDA mandates, however, that despite the accelerated approval, the drug companies verify and confirm this anticipated clinical benefit through what are called phase 4 confirmatory trials.
The evidence that allowed for the accelerated approval of Alectinib came from two phase 2 single-arm clinical trials, North America-based NP28761 (Study 1) and global study NP28673 (Study 2), in which the drug showed promising tumor response rates, as well as durations of response. A combined analysis of the two studies demonstrated that the duration of response in the CNS was 9.1 months, with an overall response rate in the CNS being 61%.
Dosage: The recommended dose for alectinib is 600 mg orally, twice daily, with food.
Side Effects: The most common side effects of Alectinib are fatigue, constipation, swelling (edema) and muscle pain (myalgia). Alectinib may cause serious side effects, including liver problems, severe or life-threatening inflammation of the lungs, very slow heartbeats and severe muscle problems. Treatment with Alectinib may cause photosensitivity and the increased risk for sunburn when patients are exposed to sunlight.
Access: Patients may contact the alectinib’s manufacturer, Genentech, for help with accessing this medication at Access Solutions (866) 4ACCESS/(866) 422-2377 or http://www.genentech-access.com for more information.
Ongoing studies: Alectinib is currently being evaluated in a global, randomized, phase 3 clinical trial called ALEX that compares alectinib to crizotinib as first line therapy for treatment-naïve ALK+ NSCLC patients. The results from this study are expected in 2018, and are expected to provide the confirmation for the full approval of alectinib for this patient subset.