Kinetics and management of adverse events associated with lorlatinib after 5 years of follow-up in the CROWN study.

objectiveWith 5 years of follow-up in the phase 3 CROWN study, lorlatinib showed unprecedented improvement in progression-free survival coupled with prolonged intracranial efficacy in patients with ALK-positive metastatic non-small cell lung cancer (mNSCLC). Here, we report kinetics and mitigation practices of select adverse events (AEs) to inform therapy management strategies.

designPost hoc safety analyses from the CROWN study assessed the incidence, prevalence, time to onset, duration, management, and resolution of hyperlipidemia, edema, weight gain, central nervous system (CNS) AEs, and peripheral neuropathy in the lorlatinib group (n = 149).

resultsAfter 5 years of follow-up, no new safety signals were observed. All-cause any-grade and grade 3/4 AEs occurred in 100% and 77% of patients, respectively; AEs led to lorlatinib dose reduction in 23% of patients, dose interruption in 62%, and permanent discontinuation in 11%. The median time to onset of any-grade hyperlipidemia was 0.5 months; 71% of events were managed with lipid-lowering agents. Median time to onset of any-grade edema, weight gain, CNS AEs, and peripheral neuropathy ranged from 2 to 4 months. Most weight gain events (95%) were mitigated with lifestyle modifications. Incidence and prevalence of CNS AEs did not increase over time; 58% of events did not require medical intervention. CONCLUSIONS AND RELEVANCE: This post hoc analysis suggests that with longer lorlatinib exposure, no new safety signals emerged, and treatment discontinuation due to AEs remained low after 5 years of follow-up. Most AEs were effectively managed with dose modifications, indicating that current management strategies can be effective to mitigate toxicity. ClinicalTrials.gov NCT03052608.