Depth of response and progression-free survival in patients with advanced ALK -positive non–small-cell lung cancer treated with lorlatinib.

8589 Background: After 5 years of follow-up in patients with ALK -positive non-small cell lung cancer (NSCLC) treated with lorlatinib, median progression-free survival (PFS) was still not reached in the phase 3 CROWN study (NCT03052608). This represents the longest PFS for any single-agent molecular targeted treatment in advanced NSCLC and all metastatic solid tumors. Depth of response (DepOR) is defined as the best percent shrinkage in tumor size compared with baseline. In this post hoc analysis of data from the CROWN study, we assessed the association between DepOR and PFS. Methods: The CROWN study is an ongoing, international, open-label, randomized, phase 3 trial comparing lorlatinib vs crizotinib in patients with previously untreated ALK -positive advanced NSCLC. Patients were randomized 1:1 to receive oral lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. This analysis examined how DepOR is associated with baseline demographics, tumor characteristics, PFS, and tumor biomarkers. Patients were evaluable for DepOR if they had target lesions at baseline and ≥1 adequate postbaseline assessment up to the time of progressive disease or new anticancer therapy. A genAI tool (12/20/24; Pfizer; GPT-4o) developed the 1st draft; authors assume content responsibility. Results: In the lorlatinib group, 142 of 149 (95%) randomized patients were evaluable for DepOR; 29 (20%) had 0%-50% DepOR, 65 (46%) had >50%-75%, and 48 (34%) had >75%-100%. Baseline demographics and tumor characteristics were similar between the DepOR groups, although the percentage of patients with baseline brain metastases was higher in the greater DepOR group. PFS improved with increasing DepOR (Table). Key biomarker analyses evaluating EML4-ALK long- and short-variant subgroups and circulating tumor DNA dynamics, based on DepOR groups, will be reported. Conclusions: Greater DepOR was associated with PFS benefit in patients with advanced ALK -positive NSCLC treated with lorlatinib. Clinical trial information: NCT03052608 . PFS in patients evaluable for DepOR (n=142). 0%-50% DepOR >50%-75% DepOR >75%-100% DepOR DepOR in the lorlatinib group, n (%) 29 (20) 65 (46) 48 (34) PFS Probability of being event free (95% CI), % At 3 years 41.0 (22.6-58.6) 68.2 (55.1-78.2) 77.5 (62.1-87.2) At 5 years 36.9 (19.3-54.7) 62.3 (48.6-73.3) 74.8 (59.0-85.2) Median (95% CI), months 12.7 (7.2-NE) NE (60.0-NE) NE (NE-NE) HR (95% CI) a 0.39 (0.21-0.73) 0.25 (0.12-0.53) NE, not evaluable. a Unstratified analysis comparison vs 0%-50% group.