Lorlatinib Improves Outcomes Over Crizotinib in First-Line Setting of ALK-Positive NSCLC

Interim analysis of the phase 3 CROWN study shows superior progression-free survival for lorlatinib compared with crizotinib in ALK-positive advanced NSCLC.

ALK rearrangements occur in an estimated 3% to 7% of NSCLCs.¹ Crizotinib (Zykadia) was the first ALK inhibitor to be approved for the treatment of patients with ALK-positive NSCLC and set the standard. Lorlatinib (Lorbrena) is a third-generation ALK tyrosine kinase inhibitor with overall and intracranial activity in ALK-positive NSCLC.¹

The CROWN study enrolled patients with stage IIIB and stage IV ALK-positive NSCLC who have had no previous treatment of metastatic disease.² Asymptomatic treated or untreated CNS metastases were allowed.¹ A total of 296 patients were randomly assigned to treatment with lorlatinib (100 mg per day, N = 149) or crizotinib (250 mg twice daily, N = 147).² As of data cutoff for the interim analysis, 103 patients treated with lorlatinib and 31 patients with crizotinib remained on study treatment.² The median follow-up for the primary end point of 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 12-month PFS was 78% with lorlatinib and 39% with crizotinib.² ORRs by BICR were 76% for lorlatinib and 58% for crizotinib, respectively.² Median DOR was not evaluable in the lorlatinib group relative to 11 months in the crizotinib group.² The intracranial ORRs by BICR were 66% with lorlatinib and 20% with crizotinib among patients with nonmeasurable brain metastasis.² Among patients with measurable brain metastasis, the intracranial ORRs were 82% and 23%, respectively.² Median time to CNS progression was not evaluable in the lorlatinib group compared with 16.6 months in the crizotinib group (P <.001).² OS was not evaluable in either study arm.² There was, however, an observed trend for a 28% improvement in OS.²

Safety and tolerability were comparable in both study groups.² Grade 3 and 4 AEs were reported in 72% of lorlatinib patients and 56% of crizotinib patients.² Serious AEs occurred in 34% and 27%, respectively.² Seven patients in each treatment arm had fatal AEs.² AEs leading to treatment discontinuation occurred in 7% and 9%, respectively, whereas 49% and 47% required temporary dose interruptions.²

According to global quality-of-life scores on the European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30, patients taking lorlatinib maintained their quality of life throughout treatment.² In contrast, those taking crizotinib experienced deterioration of quality of life over the course of the study.²

Researchers concluded that lorlatinib resulted in a statistically significant and clinically meaningful improvement in PFS compared with crizotinib and should be considered a new first-line treatment option for patients with ALK-positive NSCLC.²

References
1. Goodman A. Lorlatinib improves outcomes over crizotinib in first-line setting of ALK-positive NSCLC: CROWN trial. 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 November 30, 2020.
2. Solomon B, Bauer TM, De Marinis F, et al. Lorlatinib vs crizotinib in the first-line treatment of patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC): results of the phase III CROWN study. Ann Oncol. 2020;31(suppl_4):S1180-S1181.