First-Line Treatment with Lorlatinib Improves Outcomes Over Crizotinib in Patients with ALK-Positive NSCLC

Lorlatinib is associated with longer progression-free survival and a higher overall and intracranial response rates among patients with previously untreated, advanced ALK-positive NSCLC.

It is estimated that ALK rearrangements occur in 3% to 7% of patients with non–small-cell lung cancer (NSCLC).¹ Crizotinib was the first ALK inhibitor approved for the treatment of ALK-positive NSCLC. Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, has overall and intracranial activity in ALK-positive NSCLC.²

Patients with stage IIIB and stage IV ALK-positive NSCLC who have had no prior treatment of metastatic disease were recruited for the CROWN study.² Patients who had asymptomatic treated or untreated central nervous system metastases were eligible.² A total of 296 patients were randomized to treatment with once-daily lorlatinib 100 mg (N = 149) or twice-daily crizotinib 250 mg (N = 147).² Per the interim analysis, median follow-up for the primary end point of progression-free survival (PFS) was 18.3 months for lorlatinib and 14.8 months for crizotinib.²

Median PFS was not reached with lorlatinib compared with 9.3 months with crizotinib (P <.001) by blinded independent central review (BICR).² The lorlatinib 12-month PFS was 78% while the crizotinib PFS was 39%.² BICR-determined objective response rates were 76% for lorlatinib and 58% for crizotinib.² Median duration of response was not evaluable in the lorlatinib group; it was 11 months in the crizotinib group.² There were 78 patients with measurable or nonmeasurable brain metastasis. The intracranial objective response rate for the lorlatinib group was 66% while the crizotinib group had a rate of 20%.²

Grade 3/4 adverse event rates were 72% for lorlatinib and 56% for crizotinib.² The majority of grade 3/4 adverse events for lorlatinib were laboratory abnormalities, particularly lipid abnormalities.² Rates of discontinuation due to adverse events were 7% for lorlatinib and 9% for crizotinib.²

Researchers concluded that among patients with previously untreated, advanced ALK-positive NSCLC, lorlatinib treatment resulted in significantly longer PFS and a higher overall and intracranial response compared with crizotinib.²

References
1. Goodman A. Lorlatinib improves outcomes over crizotinib in first-line setting of ALK-positive NSCLC: CROWN trial. ASCO Post. October 25, 2020. https://ascopost.com/issues/october-25-2020/lorlatinib-improves-outcomes-over-crizotinib-in-first-line-setting-of-alk-positive-nsclc-crown-trial. Accessed January 11, 2021.
2. Shaw A, et al. N Engl J Med. 2020;383:2018-2029.