Clinical trials of lorlatinib/lorlatinib

The phase 3 CROWN trial (NCT03052608) focuses on patients with previously untreated ALK-positive non-small cell lung cancer. 1 Patients were randomized 1:1 to receive lorlatinib 100 mg orally once daily or crizotinib 250 mg orally twice daily. Patients were stratified according to the presence of brain metastases and race. The trial's primary endpoints were progression-free survival (PFS) and cumulative incidence of central nervous system (CNS) progression by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed PFS, and objective response rate.

The median PFS (NR) in patients with brain metastases was not reached in the lorlatinib group, compared with 7.2 months in the crizotinib group. The differences in 12-month PFS rates were 78% (95% CI, 60%-88%) and 22% (95% CI, 9%-39%; HR, 0.20, 95% CI, 0.10-0.43; p<0.0001). In patients without brain metastases, median PFS was NR vs 11.0 months. The 12-month PFS rates were 78% (95% CI, 69%-85%) and 45% (95% CI, 34%-55%; HR, 0.32, 95% CI, 0.20-0.49; p<0.0001).

In terms of the incidence ofCNS progression, among patients with baseline brain metastases, the 12-month incidence rates for lorlatinib and crizotinib were 7% and 72%, respectively (HR, 0.0 7; 95% CI, 0.02-0.24), among patients without brain metastases at baseline, 1% in the lorlatinib group and 18% in the crizotinib group (HR, 0.05; 95% CI, 0.01-0.42).

Adverse reactions related to central nervous system progression occurred in 35% of lorlatinib patients and 11% of crizotinib patients. Grade 1 AEs occurred in 62% and 73% of patients in the lorlatinib group and crizotinib group, respectively. Grade 2 AEs occurred in 29% and 27% of patients in the lorlatinib group. Grade 3 AEs occurred in 10% of patients in the lorlatinib group. These include cognitive effects, emotional effects, verbal effects and psychotic effects.

The experience of lorlatinib in second-line treatment is that lorlatinib has obvious comorbidities. Particularly for patients with ALK-positive disease, who are likely to receive first-line therapy for a long period of time, alectinib was much better tolerated. All the data for ALK-positive disease show very low response rates to chemotherapy, but that's the standard of care. These drugs have not yet been proven to cure patients with ALK-positive NSCLC, whereas chemotherapy has been shown to cure patients.