Frontline Alectinib Recommended for EU Approval for ALK+ NSCLC

Sandra Horning, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of alectinib (Alecensa) for the first-line treatment of adults with ALK-positive, advanced non—small cell lung cancer (NSCLC).

Based on phase III results from the ALEX trial showing that the second-generation ALK-inhibitor significantly reduced the risk of progression or death compared with crizotinib (Xalkori), the agency has also simultaneously recommended converting the current conditional marketing authorization for alectinib following failure with crizotinib to a full marketing authorization.

In the ALEX study, alectinib significantly improved progression-free survival (PFS) by 53% (hazard ratio [HR], 0.47; 95% CI, 0.34-0.65; P <.001) compared with crizotinib. The primary endpoint of investigator-reported median PFS has not been reached in the alectinib arm (95% CI, 17.7-not reached) compared with 11.1 months (95% CI, 9.1-13.1) in the crizotinib arm.

“This is more great news for people with this type of lung cancer, bringing them closer to benefiting from Alecensa’s superior efficacy earlier in their treatment journey,” Sandra Horning, MD, Roche’s chief medical officer and head of global product development, said in a press release. “The results from ALEX clearly showed the significant benefits of Alecensa over crizotinib and we are pleased this has been recognized by the CHMP.”

The drug now goes to the European Commission for final consideration. A positive decision would make alectinib available across Europe in both the first-line and second-line settings. The FDA granted priority review status to first-line alectinib in August. The drug is approved in the United State for use in patients with ALK-positive NSCLC following failure on crizotinib.

ALEX is the second phase III trial to show that alectinib outperforms crizotinib in frontline ALK-positive NSCLC. Alectinib improved PFS by 66% versus crizotinib in the Japanese open-label phase III J-ALEX study, which was presented at the 2016 ASCO Annual Meeting.

ALEX is a randomized, multicenter, open-label phase III study comparing alectinib versus crizotinib for efficacy and safety in treatment-naïve patients with ALK-positive NSCLC. A total of 303 patients were randomly assigned 1:1 to alectinib or crizotinib at 161 sites around the world. Secondary endpoints included time to central nervous system (CNS) progression, objective response rate, duration of response, overall survival (OS), health-related quality of life, and safety.

Alectinib reduced the risk for brain or CNS metastasis by 84% compared with crizotinib (HR, 0.16; 95% CI; 0.10-0.28; P<.001). 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) in the alectinib arm compared with 41.4% (95% CI, 33.2-49.4) in the crizotinib arm.

OS data are still immature with only about a quarter of events being reported.

The safety and tolerability profile of alectinib was superior to crizotinib despite the longer duration of treatment (17.9 vs. 10.7 months). Patients assigned to alectinib were less likely to experienced grade ≥3 adverse events (AEs), 41% versus 50%.

The most common grade ≥3 AEs (≥5%) in the alectinib arm were increased alanine transferase and aspartate transferase (5%) and decreased red blood cells (5%). Patients assigned to crizotinib were more likely to discontinue treatment due to AEs (13% vs 11%), and more likely to experience dose reduction (21% vs 16%) and dose interruption (25% vs 19%).

CHMP recommends EU approval of Roche’s Alecensa (alectinib) as a first-line treatment for people with ALK-positive NSCLC. Roche. http://bit.ly/2xEeXwm. Accessed October 13, 2017.