Impact of lorlatinib dose modifications on adverse event outcomes in the phase 3 CROWN study.

8590 Background: In an updated analysis of the CROWN study (NCT03052608), after 5 years of follow-up, lorlatinib continued to show superior efficacy over crizotinib in patients with previously untreated advanced ALK + non-small cell lung cancer (NSCLC), with median progression-free survival (PFS) still not reached. A post hoc analysis of CROWN found no impact on PFS or time to intracranial progression with lorlatinib dose reductions within the first 16 weeks. These findings underscore the importance of dose modifications to mitigate toxicity and maintain long-term treatment efficacy. The objective of this analysis was to further characterize lorlatinib dose reductions and their impact on safety and adverse event (AE) outcomes. Methods: The CROWN study is an ongoing, international, open-label, randomized phase 3 trial comparing lorlatinib vs crizotinib in patients with previously untreated advanced ALK + NSCLC. Patients were randomized 1:1 to receive lorlatinib 100 mg once daily (QD; n=149) or crizotinib 250 mg twice daily (n=147). This post hoc analysis used data from the 5-year follow-up to assess time to dose reduction, duration of treatment with reduced dose, and its impact on AEs and outcomes associated with lorlatinib. A genAI tool (12/13/24; Pfizer; GPT-4o) developed the 1st draft; authors assume content responsibility. Results: At 5 years of follow-up, 49 of 149 patients in the lorlatinib arm had ≥1 lorlatinib dose reduction. Treatment is ongoing in 33% of patients who had 1 dose reduction (n=24) and in 20% who had 2 dose reductions (n=25). In patients who had 1 dose reduction to 75 mg QD, median time to dose reduction was 7.1 months (range, 1.7-64.8), and median duration of treatment with the 75-mg dose was 42.2 months (range, 0.2-68.3). In patients who had 2 dose reductions (dose reduced to 75 mg QD and then again to 50 mg QD), median time to second dose reduction was 11.3 months (range, 2.5-56.9), and median duration of treatment with the 50-mg dose was 20.7 months (range, 0.5-61.8). In patients who had 1 or 2 dose reductions, all-cause AEs associated with dose reductions are shown in the table. Of the 30 AEs leading to 1 dose reduction, 27% of events resolved and 13% partially resolved. Of the 59 AEs leading to 2 dose reductions, 46% of events resolved and 5% partially resolved. Conclusions: This post hoc analysis of the CROWN study showed that dose reductions were effective in managing AEs associated with lorlatinib. These findings show the importance of dose modifications to mitigate toxicity and continue lorlatinib treatment for prolonged periods of time in patients with advanced ALK + NSCLC. Clinical trial information: NCT03052608 . AEs associated with dose reductions in >2 patients, n (%) Any grade Grade ≥3 1 dose reduction (n=24) Any 23 (96) 14 (58) Peripheral edema 4 (17) 2 (8) 2 dose reductions (n=25) Any 24 (96) 11 (44) Peripheral edema 6 (24) 0 Blood triglycerides increased 3 (12) 2 (8) Disturbance in attention 3 (12) 0 Generalized edema 3 (12) 1 (4)