The FDA approved alectinib as first-line therapy for ALK-positive non-small cell lung cancer based on results of the ALEX study, which showed significant improved PFS compared with crizotinib.
Clinicians now have a new first-line therapy that may significantly improve care for patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). On November 6, 2017, the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application for alectinib for this patient population as detected by an FDA-approved test.
The approval is based on results from the phase III ALEX study, which showed alectinib significantly improved progression-free survival (PFS) compared with crizotinib as assessed by independent review committee. In this study, the median PFS was 25.7 months for patients who received alectinib compared with 10.4 months for patients who received crizotinib.
The study also showed that alectinib had a significant 84% risk reduction of metastasis to the brain or central nervous system (CNS) compared with crizotinib (hazard ratio, 0.16; 95% CI, 0.10-0.28; P < .0001). This was based on a time to CNS progression analysis in which there was a lower risk of progression in the CNS as the first site of disease progression for patients who received alectinib (12%) compared with crizotinib (45%).
Clinical trial investigator D. Ross Camidge, MD, PhD, from the University of Colorado Cancer Center, said this trial shows how the brain has become an indisputable battleground for defining the best drug in this patient population. “These data will significantly influence how we do clinical research, ensuring, as in the ALEX trial, that CNS endpoints are given much more prominence in the future in malignancies with a very high rate of CNS metastases like lung cancer,” Dr. Camidge told OncoTherapy Network.
Lung cancer expert Sally York, MD, PhD, assistant professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, said this approval is a significant advance. However, she noted that much more work is needed to improve outcomes for patients with ALK-positive metastatic NSCLC.
"Approval of alectinib as first-line therapy is an important step in our ongoing effort to improve outcomes for our lung cancer patients. Alectinib was found to be superior to crizotinib, and importantly, demonstrated the ability to delay or prevent brain metastases, which can be a devastating complication of lung cancer. We need ongoing trials to help us determine the best sequence of therapies, but this is significant progress in the right direction," Dr. York told OncoTherapy Network.
Alectinib received Breakthrough Therapy Designation from the FDA in September 2016 for the treatment of adults with advanced ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor. The FDA also converted alectinib’s initial accelerated approval in December 2015 for treating ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib (second-line) to a full approval.
The ALEX study is an open-label, randomized, active-controlled, multicenter, phase III study. This trial is evaluating the efficacy and safety of alectinib versus crizotinib in patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease and whose tumors were characterized as ALK-positive by the VENTANA ALK (D5F3) CDx Assay, an immunohistochemistry test.
The multicenter study was conducted in 303 patients (152 received alectinib; 151 received crizotinib) across 161 sites in 31 countries. Overall survival data are currently considered immature with only about a quarter of events being reported.
In this trial, grade ≥ 3 adverse reactions were reported for 41% of patients treated with alectinib. The most common were increased creatinine, hyperbilirubinemia, hyponatremia, aspartate transaminase, alanine transaminase and anemia.