Today I’ll be presenting on behalf of my co-investigators the primary results of the ALEX study, a global randomised phase III study of alectinib versus crizotinib as first line therapy for advanced ALK positive lung cancer. ALK, or anaplastic lymphoma kinase, was first discovered as a target in lung cancer about ten years ago. This target is found in approximately 5% of lung cancer patients which translates into about 50,000 new cases of ALK positive lung cancer worldwide each year. The current standard of care for patients with newly diagnosed advanced ALK positive lung cancer is the first generation ALK inhibitor crizotinib. While crizotinib can be very effective initially most patients will develop worsening disease within the first year of treatment. One of the most common sites of worsening disease is the brain or central nervous system and this likely reflects the drug’s poor penetration into the brain.
Alectinib is a next generation ALK inhibitor that is more potent and more brain penetrant than crizotinib. In early phase studies alectinib demonstrated robust clinical activity in both crizotinib naïve and crizotinib resistant ALK positive patients. In fact, alectinib is already approved in the US and other countries for ALK positive patients who have failed prior crizotinib. Based on these prior studies we hypothesised that in a randomised head-to-head comparison alectinib would be more effective than crizotinib as first line treatment for patients with advanced ALK positive lung cancer.
Shown here is the study design for ALEX. This was a global study involving 98 sites and 29 countries around the world. A total of 303 ALK positive patients were enrolled. All patients had advanced or metastatic disease and were in the first line setting. Patients with treated or untreated brain metastases were eligible for the study. Patients were randomised one to one to receive either alectinib or crizotinib. The primary endpoint of the study was progression free survival, PFS, based on investigator assessment. Secondary endpoints are listed here and in the interests of time I’m going to highlight just the primary endpoint and three of the key secondary endpoints – progression free survival by independent review, time to CNS progression and safety.
As shown here, ALEX met its primary endpoint and showed that alectinib is superior to crizotinib in prolonging progression free survival. Median PFS was 11.1 months with crizotinib and not reached with alectinib. The hazard ratio was 0.47 in favour of alectinib and this corresponds to a 53% reduction in the risk of progression. This difference was highly statistically significant with a p-value of less than 0.0001. Similar findings were obtained by the independent review committee. Based on independent review median PFS was 10.4 months with crizotinib and 25.7 months with alectinib, a more than doubling of progression free survival.
One of the key secondary endpoints in the ALEX study was time to progression in the CNS. Patients treated with alectinib had a significantly lower incidence of CNS progression compared to those treated with crizotinib. The cause-specific hazard ratio was 0.16, corresponding to an 84% reduction in the risk of having CNS progression. As shown here at twelve months the cumulative incidence of CNS progression was 9% in the alectinib group as compared to 41% in the crizotinib group. These findings show that alectinib can significantly delay disease progression in the brain compared with crizotinib.
On the right is shown another key secondary endpoint of the study which is safety. Overall there were fewer severe side effects with alectinib compared to crizotinib. As a result fewer patients required dose reduction, dose interruption or treatment discontinuation.
In conclusion, the ALEX study is the first global head-to-head trial comparing a next generation ALK inhibitor with a first generation ALK inhibitor as first line therapy for advanced ALK positive lung cancer. This study met its primary endpoints and showed significantly longer progression free survival with alectinib compared to crizotinib. There was a 53% reduction in the risk of progression. In addition, alectinib was superior to crizotinib in treating and in preventing brain metastases; there was an 84% reduction in the risk of CNS progression. Taken together, both the efficacy and safety results of this study establish alectinib as the new standard of care for patients with advanced previously untreated ALK positive lung cancer. Thank you.
