Comparing the Brain Efficacy of Lorlatinib and Crizotinib in ALK-Positive Lung Cancer

The ALK (anaplastic lymphoma kinase) receptor in humans is encoded by the ALK gene and is responsible for growth and proliferation. The ALK gene, together with the EML4 gene, can trigger lung cancer when they fuse. This is one of the important causes of lung cancer in people who do not smoke.

The EML4-ALK fusion gene accounts for non-small cell lung cancers (KHDAK) in approximately 5% of cases. This proportion may seem small, but considering the worldwide incidence of lung cancer, it corresponds to 70 thousand new lung cancer patients each year.

The ALK gene was discovered in 1977. In 1983, ALK was found to be associated with non-small cell lung cancer (KHDAK) and lymphoma. In 2007, the ALK-EML4 fusion mutation was identified in KHDAK. In 2011, crizotinib (Xalkori), the first targeted drug for ALK-positive lung cancer, received FDA (US Food and Drug Administration) approval. In subsequent years, ceritinib, alectinib, brigatinib and, finally, lorlatinib received FDA approval for ALK-positive lung cancer.

Advanced ALK-positive lung cancers tend to metastasize (spread) to the brain, and the disease course is known to be less favorable after cancer spreads to the brain. Targeted drugs developed against ALK fusions differ in their efficacy against brain metastases.

Journal of Clinical Oncology reported the phase III CROWN study on July 9, 2022. Compared with crizotinib, lorlatinib significantly improved progression-free survival and the risk of brain metastasis progression in previously untreated patients with advanced ALK-positive lung cancer, with or without brain metastases at diagnosis.

Lorlatinib received FDA approval as first-line treatment for advanced ALK-positive lung cancer on March 3, 2021. Lorlatinib also has a license from the Republic of Turkey Ministry of Health for first-line treatment of advanced ALK-positive lung cancer in Turkey.

Details of the CROWN Study

In the study, patients were randomly assigned to receive lorlatinib 100 mg once daily (149 patients) or crizotinib 250 mg twice daily (147 patients); crossover between drug groups was not permitted.

Brain metastases were present at baseline in 38 patients (26%) in the lorlatinib group and 40 patients (27%) in the crizotinib group. Of these patients, 8 (21%) and 10 (25%), respectively, had previously received brain radiotherapy.

Key Findings

Among patients with brain metastases at baseline, median progression-free survival was not reached because more than half of those receiving lorlatinib continued to respond to treatment. In the Krizitonib arm, this duration was 7.2 months.

Lorlatinib reduced the risk of cancer progression by 80% (hazard ratio [HR] = 0.20, 95% CI = 0.10–0.43, P < 0.0001).

The 12-month progression-free survival rate was 78% in the lorlatinib arm versus 22% in the crizotinib arm.

Median progression-free survival was not reached in patients without brain metastases at baseline who received lorlatinib. In contrast, this duration was 11 months with crizotinib. The 12-month progression-free survival rates in this group were 78% versus 45%.

The cumulative incidence of brain progression was 7% versus 72% in patients with brain metastases at baseline, and 1% versus 18% in those without baseline metastases.

Drug-related brain side effects occurred in 35% of patients in the lorlatinib group and 11% in the crizotinib group (grade 1-2 mild side effects: 90% versus 100%; grade 3 serious side effects: 10% versus 0%). Of the total 86 adverse events in the lorlatinib group, 62% were managed without intervention and 23% with lorlatinib dose modification (reduction or interruption), with or without concomitant medication; lorlatinib was discontinued in two patients.

Conclusion

As first-line treatment, lorlatinib improved progression-free survival outcomes and reduced brain progression compared with crizotinib in patients with advanced ALK-positive non-small cell lung cancer, with or without brain metastases at baseline. Half of all brain adverse events resolved without intervention or with lorlatinib dose modification.