The European Union’s ( EU ) Committee for Medicinal Products for Human Use ( CHMP ) has adopted a positive opinion recommending the approval of Alecensa ( Alectinib ) as a monotherapy for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer ( NSCLC ).
It has also simultaneously recommended the conversion of the current conditional marketing authorisation for Alecensa in Crizotinib failure ( second-line ) to a full marketing authorisation.
The CHMP recommendation in first-line is based on results from the global phase III ALEX study, which showed Alectinib significantly reduced the risk of disease worsening or death ( progression-free survival, PFS ) by 53% ( hazard ratio, HR=0.47, 95% CI: 0.34-0.65, p less than 0.001 ) compared with Crizotinib.
The study also showed that Alectinib reduced the risk of tumours spreading to, or growing in, the brain or central nervous system ( CNS ) by 84% ( HR=0.16, 95% CI: 0.10-0.28, p less than 0.001 ), compared with Crizotinib.
The safety and tolerability profile of Alectinib compared favourably to that of Crizotinib despite the longer duration of treatment with Alectinib ( 17.9 vs. 10.7 months ), and was consistent with that observed in previous studies.
ALEX is a randomised, multicentre, open-label phase III study evaluating the efficacy and safety of Alectinib versus Crizotinib in treatment-naïve people with ALK-positive NSCLC whose tumours were characterised as ALK-positive by the VENTANA ALK ( D5F3 ) CDx Assay, a companion immunohistochemistry ( IHC ) test developed by Roche Tissue Diagnostics.
People were randomised ( 1:1 ) to receive either Alectinib or Crizotinib.
The primary endpoint of the ALEX study is PFS as assessed by the investigator, and secondary endpoints include: Independent Review Committee (IRC)-assessed PFS, time to CNS progression, objective response rate ( as defined by RECIST criteria ), duration of response, overall survival, health-related quality of life and safety.
The multicentre study was conducted in 303 people across 161 sites in 31 countries.
Alectinib has reduced the risk of disease worsening or death ( PFS ) by 53% compared to Crizotinib ( HR=0.47, 95% CI: 0.34-0.65, p less than 0.001 );
Investigator-reported median PFS ( the primary endpoint ) was not yet reached in the Alectinib arm ( 95% CI: 17.7 -not reached ) versus 11.1 months ( 95% CI: 9.1-13.1 months ) in the Crizotinib arm. IRC-reported median PFS ( a secondary endpoint ) was 25.7 months ( 95% CI: 19.9-not estimable ) in the Alectinib arm versus 10.4 months ( 95% CI: 7.7-14.6 months ) in the Crizotinib arm ( HR=0.50, 95% CI: 0.36-0.70; p less than 0.001 );
Alectinib has reduced the risk of progression in the CNS by 84% ( HR=0.16, 95% CI: 0.10-0.28; p less than 0.001 );
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% ) for people treated with Alectinib and 41.4% ( 95% CI: 33.2-49.4% ) for people treated with Crizotinib;
Overall survival ( OS ) data are still immature with only about a quarter of events being reported;
Grade 3-5 adverse events were less frequent in the Alectinib arm ( 41% ) compared with the Crizotinib arm ( 50% ). In the Alectinib arm, the most common grade 3-5 adverse reactions ( greater than or equal to 5% ) were increased liver enzymes ( alanine transferase and aspartate transferase; 5% ) and decreased red blood cells ( anaemia; 5% );
Adverse effects 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 with the Crizotinib arm. ( Xagena )
Source: Roche, 2017