FDA Grants Alectinib Priority Review for Initial Treatment of ALK-Positive Lung Cancer

Today, the U.S. Food and Drug Administration (FDA) accepted Genentech’s supplemental New Drug Application (sNDA) and granted Priority Review for alectinib (Alecensa) as a first-line treatment for people with anaplastic lymphoma kinase (ALK)-positive, locally advanced, or metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test. The FDA will make a decision on approval by November 30, 2017.

“Phase III results showed alectinib reduced the risk of disease worsening by more than half compared to the current standard of care, and lowered the risk of tumors spreading to or growing in the brain by more than 80%,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development at Genentech. “We are working closely with the FDA to bring this medicine as an initial treatment for people with ALK-positive NSCLC as soon as possible.”

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. Breakthrough Therapy designation was granted on the basis of the phase III J-ALEX trial.

Alectinib was granted accelerated approval by the FDA in December 2015 for the treatment of people with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib (Xalkori).

This sNDA submission for alectinib is based on results from the phase III ALEX and phase III J-ALEX studies. Results from the ALEX study (LBA9008) and updated results from the J-ALEX study (Abstract 9064) were recently presented at the 2017 ASCO Annual Meeting.

ALEX Study

ALEX is a randomized, multicenter, open-label phase III study evaluating the efficacy and safety of alectinib vs crizotinib in treatment-naive patients with ALK-positive NSCLC whose tumors were characterized as ALK-positive by the VENTANA ALK (D5F3) CDx Assay, a companion immunohistochemistry test.

Patients were randomized (1:1) to receive either alectinib or crizotinib. The multicenter study was conducted in 303 people across 161 sites in 31 countries.

Alectinib reduced the risk of disease worsening or death (progression-free survival) by 53% compared to crizotinib (hazard ratio [HR] = 0.47, 95% confidence interval [CI] = 0.34–0.65, P < .0001). Investigator-reported median progression-free survival, the primary endpoint, was not yet reached in the alectinib arm (95% CI = 17.7–not reached) vs 11.1 months (95% CI = 9.1–13.1 months) in the crizotinib arm.

Independent Review Committee–reported median progression-free survival, a secondary endpoint, was 25.7 months (95% CI = 19.9–not reached) in the alectinib arm vs 10.4 months (95% CI = 7.7–14.6 months) in the crizotinib arm (HR = 0.50, 95% CI = 0.36–0.70, P < .0001).

Alectinib reduced the risk of progression in the central nervous system (CNS) by 84% (HR = 0.16, 95% CI = 0.10–0.28, P < 0.0001) vs crizotinib. The 12-month cumulative rate of CNS progression for people with or without existing CNS metastases at baseline was 9.4% (95% CI = 5.4–14.7 percent) for people treated with alectinib and 41.4% (95% CI = 33.2–49.4%) for people treated with crizotinib.

Overall survival data are currently considered immature with only about one-quarter of events being reported.

Grade 3 to 5 adverse events were less frequent in the alectinib arm (41%) compared to the crizotinib arm (50%). In the alectinib arm, the most common grade 3 to 5 adverse events (≥ 5%) were increased liver enzymes (alanine transferase and aspartate transferase; 5%) and decreased red blood cells (anemia; 5%). Adverse events leading to discontinuation (11% vs 13%), dose reduction (16% vs 21%), and dose interruption (19% vs 25%) were all lower in the alectinib arm compared to the crizotinib arm.

J-ALEX Study

The J-ALEX study is an open-label, randomized phase III study conducted by Chugai that compared the efficacy and safety of alectinib with crizotinib in Japanese patients. J-ALEX enrolled 207 patients with ALK-positive, advanced, or recurrent NSCLC who had not been treated with an ALK inhibitor. People were randomized to the alectinib group or the crizotinib group on a one-to-one ratio.

In this study, alectinib reduced the risk of disease worsening or death by 62% compared to crizotinib (HR = 0.38, 95% CI = 0.2–0.55, P < .0001). The median progression-free survival was 25.9 months in the alectinib arm (95% CI = 20.3–not reached) vs 10.2 months (95% CI = 8.3–12.0 months) in the crizotinib arm. Alectinib reduced the risk of progression in the CNS by 81% (HR = 0.19, 95% CI = 0.07–0.53) in people without brain metastases at baseline, and reduced the risk of CNS progression by 49% (HR =0.51, 95% CI: 0.16–1.64) in patients with brain metastases at baseline.

Grade 3 to 4 adverse events were less frequent in the alectinib arm (32%) compared to the crizotinib arm (57%). In the alectinib arm, the most common grade 3–4 adverse events (≥ 5%) were an increase in muscle enzymes (blood creatine phosphokinase increase; 5%) and interstitial lung disease (5%). AEs leading to discontinuation (11% vs 23%) and dose interruption (29% vs 64%) were lower in the alectinib arm compared to the crizotinib arm.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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