The outcomes of first-line lorlatinib versus crizotinib in advanced ALK-positive non-small cell lung cancer

The study compared outcomes of lorlatinib (Lorbrena) with crizotinib (Xalkori) in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) with ALK mutations (genetic abnormalities). The main finding was that patients receiving lorlatinib had longer progression-free survival (PFS) and a higher response in the brain.

ALK-positive advanced NSCLC has an abnormality in the ALK gene. The ALK gene makes a protein involved in cell growth. Cancers with mutated (changed) ALK genes are more likely to spread. Crizotinib is a first-generation ALK inhibitor that has been traditionally used in first-line or as initial therapy for such tumors. Lorlatinib is a third-generation ALK-inhibitor that promises to treat cancer progression in the central nervous system (CNS; brain and spine) more effectively. It is currently approved for patients who fail in responding to other ALK-inhibitors. However, the outcomes of first-line lorlatinib versus crizotinib in ALK-positive advanced NSCLC are unknown.

The study included 296 previously untreated adult patients with ALK-positive advanced NSCLC. 149  patients were randomly assigned to receive lorlatinib and 147 patients were assigned to receive crizotinib. The cancer had spread to the CNS in 26% of patients from the lorlatinib group and 27% from the crizotinib group. The average follow-up for the lorlatinib group was 18.3 months and 14.8 months in the crizotinib group. 

The survival rate without cancer worsening after 12 months was 78% with lorlatinib and 39% with crizotinib. Lorlatinib was associated with a 72% lower risk of cancer progression.

76% of patients in the lorlatinib group responded to treatment compared to 58% in the crizotinib group. 70% of patients receiving lorlatinib and 27% receiving crizotinib had their response last for at least 12 months. In patients with cancer spread to the brain, 66% of those treated with lorlatinib and 20% with crizotinib responded to treatment. The percentage of patients alive without CNS progression at 12 months was 96% with lorlatinib and 60% with crizotinib.

The most common side effects with lorlatinib were high blood-fat levels, swelling, increased weight, or numbness and tingling in the feet. The frequency of moderate to severe side effects was 72% in the lorlatinib group and 56% in the crizotinib group. 7% in the lorlatinib group and 9% of the crizotinib group stopped treatment due to side effects.

The study concluded that first-line lorlatinib increased survival without cancer progression and improved response in the brain in patients with ALK-positive advanced NSCLC, compared to crizotinib. 

This study had a short follow-up period. Longer-term studies are needed. This study is sponsored by Pfizer, the manufacturer of both lorlatinib and crizotinib.