Lorlatinib vs crizotinib as first-line treatment for advanced <i>ALK</i> + non-small cell lung cancer: 7-year update from the phase 3 CROWN study.

Abstract

8502 Background: Median progression-free survival (PFS) was not reached (NR) with lorlatinib in the phase 3 CROWN study after 5 yrs of f/u, representing the longest PFS reported in advanced non-small cell lung cancer (NSCLC). Due to the unprecedented PFS benefit with lorlatinib after 5 yrs of f/u and the decreased event rate after the first 24 mos in the study, we aimed to quantify long-term outcomes at 7 yrs. Methods: 296 treatment-naive patients (pts) with advanced ALK + NSCLC were randomized 1:1 to receive lorlatinib 100 mg once daily (n=149) or crizotinib 250 mg twice daily (n=147). This post hoc analysis presents investigator-assessed efficacy outcomes, safety, and biomarker analyses. Formal statistical testing between arms was not performed. Results: As of October 31, 2025, 66 of 149 pts (44%) vs 4 of 142 (3%) were receiving lorlatinib vs crizotinib. With a median f/u for PFS (95% CI) of 83.0 (81.2-86.3) and 77.2 mos (36.8-not evaluable), respectively, median PFS (95% CI) was NR (68.5-NR) with lorlatinib and 9.1 mos (7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.26); the 7-yr PFS (95% CI) was 55% (46-63) and 3% (1-8). In the lorlatinib arm, pts without a PFS event at the end of 24 mos had a 79% probability of survival without progression at yr 7. PFS benefit was consistent across all prespecified subgroups. No new intracranial (IC) progression events occurred after the first 30 mos on lorlatinib. Median time to IC progression (95% CI) was NR (NR-NR) with lorlatinib and 16.4 mos (12.7-21.9) with crizotinib (HR, 0.06; 95% CI, 0.03-0.12). The number of overall survival (OS) events for a protocol-specified analysis has not been met; OS f/u is still ongoing. The safety profile was consistent with the 5-yr results, with all-cause grade 3/4 adverse events (AEs) in 77% of pts with lorlatinib and 57% with crizotinib. Treatment-related AEs (TRAEs) led to permanent treatment discontinuation in 5% of pts with lorlatinib and 6% with crizotinib. No new permanent discontinuations due to TRAEs occurred after the first 26 mos with lorlatinib. Dose reductions were reported in 34% of pts in the lorlatinib arm (17% had 1 dose reduction and 17% had 2 reductions). Long-term efficacy was similar between pts with and without dose reduction. Exploratory translational analyses of outcomes in pts with different molecular subtypes and resistance mechanisms at the end of treatment are ongoing. Conclusions: With median PFS yet to be reached after 7 yrs of f/u in CROWN, lorlatinib continues to show unprecedented and highly durable benefit in treatment-naïve pts with advanced ALK + NSCLC. In pts without a PFS event at 24 mos, the probability of survival without progressive disease at 7 yrs was 79%. Longer f/u showed very few additional PFS events, no new IC progression, and no new treatment-related discontinuation, suggesting long-term substantial benefit with lorlatinib for the majority of pts with advanced ALK + NSCLC. Clinical trial information: NCT03052608 .