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Breakthrough therapy designation for Roche’s lung cancer drug alectinib - drugdiscovery.com


Breakthrough therapy designation for Roche’s lung cancer drug alectinib - drugdiscovery.com
The FDA has granted breakthrough therapy designation for Roche’s promising investigational 2nd generation ALK inhibitor, used for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) that has progressed on crizotinib. Lung cancer is currently the most common malignant disease worldwide surpassing breast, colon, pancreas, and prostate cancer death rates. According to histological classifications, non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung tumours. By using standard chemotherapeutic regimens tailored to histology results, the overall 5-year survival percentage is poor, about 15%. Therefore, novel genotype-based treatments were developed which target the two most frequent mutations found in NSCLC. One mutation affects the anaplastic lymphoma kinase (ALK) fusion gene that encodes a receptor tyrosine kinase of the insulin receptor superfamily. Altered expression and hyperactivation of ALK as a consequence of translocations or point mutations is a decisive oncogenic lesion in NSCLC.

Crizotinib represents the first generation of ALK inhibitors acting competitively within the ATP-binding pocket of the kinase. Unfortunately, intrinsic or acquired tumour resistance to crizotinib often renders the drug therapy ineffective. Additionally, in patients with NSCLC, brain metastases are typically found probably because the poor penetration of crizotinib through the blood-brain barrier. This type of tumour progression is substantial contributing factor to the morbidity and mortality observed in NSCLC.

Hence, a new generation ALK inhibitors were developed to bypass the resistance. Alectinib, a prominent member of this class, is a potent, selective, and orally available inhibitor of ALK with ten-fold greater potency than crizotinib. A single-arm, open-label, phase I/II trial was conducted in Japan to investigate the safety and activity of alectinib with ALK mutation positive recurrent or advanced NSCLC with a treatment history of one or more chemotherapy regimens. In phase I, the safety, tolerability, pharmacokinetic parameters and recommended dose of alectinib were assessed. Since no dose-limiting toxicities were observed, the highest dose (300 mg twice a day) was subsequently used in the phase II portion of the study. 46 Japanese patients were treated, of whom 43 achieved an objective response (93.5%) including 2 complete and 41 partial tumour remissions. The progression free survival rate at 12 months was measured as 83%. Remarkably, among the 15 patients entered the study with brain metastases no progression of the lesions was observed during the trial indicating that alectinib can cross the blood-brain barrier and reaches effective tissue level in the central nervous system. Since brain metastases occur in about half of all NSCLC patients, this clinically documented activity of alectinib provides a new therapeutic avenue to control this challenging condition, beyond conventional treatments such as radiotherapy, radiosurgery, and neurosurgical resection.

The most frequent alectinib treatment-related adverse events were liver function test abnormalities, neutropenia, rash, constipation, stomatitis, nausea and myalgia.

Alectinib has recently been approved in Japan for the specifically targeted treatment of ALK mutant NSCLC patients. Previously, the drug was also granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in June 2013 for patients with ALK-positive, crizotinib-refractory NSCLC.

By Ferenc Zsila M.D., Ph.D.

Tags: alectinib, lung cancer, breakthrough therapy designation, Roche, investigational drug, ALK inhibitor, metastatic non-small cell lung cancer, NSCLC, FDA - September 23, 2013


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