Longest ever PFS in advanced NSCLC CROWNs lorlatinib’s 5-year data

After 5 years of follow-up, median progression-free survival (PFS) has still not been reached in patients with advanced non-small-cell lung cancer (NSCLC) treated with lorlatinib in the phase III CROWN study, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumours.

CROWN is an ongoing, randomized, global phase III study, in which 296 patients with stage IIIB/IV ALK+ NSCLC who did not receive prior systemic treatment were randomized 1:1 to receive either lorlatinib 100 mg QD or crizotinib 250 mg BID. The primary endpoint is PFS by blinded independent central review.

“After a median follow-up of 60.2 months in the lorlatinib arm and 55.1 months in the crizotinib arm, lorlatinib vs crizotinib hazard ratio [HR] for PFS was 0.19 [95 percent confidence interval (CI), 0.13–0.27]. Median PFS was not reached with lorlatinib and 9.1 months with crizotinib. At the landmark of 5 years, the respective PFS rates were 60 and 8 percent,” reported Dr Benjamin Solomon of Peter MacCallum Cancer Center in Melbourne, Australia. The PFS benefit with lorlatinib was observed irrespective of presence of brain metastases, ethnic origin, sex, age, or smoking status. [Solomon BJ, et al, ASCO 2024, abstract LBA8503]

Baseline brain metastases were present in approximately a quarter of patients. In patients with baseline brain metastases, the HR for disease progression or death was 0.08 (95 percent CI, 0.04–0.19), while in those without, the HR was 0.24 (95 percent CI, 0.16–0.36), both in favour of lorlatinib. In both groups, the median PFS had not been reached with lorlatinib.

Following a baseline brain MRI, scans were subsequently performed every 8 weeks in all patients throughout the study. In the overall population, investigator-assessed median time to intracranial (IC) progression had not been reached in the lorlatinib group and was 16.4 months with crizotinib (HR, 0.06; 95 percent CI, 0.03–0.12). “There was a 92 percent probability of being IC progression–free with lorlatinib vs 21 percent with crizotinib at 5 years,” said Solomon.

Time to IC progression was longer with lorlatinib in the presence (HR, 0.03; 95 percent CI, 0.01–0.13) or absence (HR, 0.05; 95 percent CI, 0.02–0.13) of baseline brain metastases. “These results speak to the ability of lorlatinib not only to prevent progression of existing brain metastases, but also to prevent the development of new brain metastases,” remarked Solomon.

Lorlatinib’s safety profile was consistent with that observed in earlier analyses. Grade 3/4 adverse events (AEs) were seen in 77 percent of patients treated with lorlatinib vs 57 percent of patients treated with crizotinib. “The higher incidence of grade 3/4 AEs [in the lorlatinib arm] was largely due to elevations of triglycerides [25 percent] and cholesterol [21 percent], weight gain [23 percent], and hypertension [12 percent],” highlighted Solomon.

AEs led to lorlatinib dose reductions in 23 percent of patients. “Given the utility of dose reductions in managing AEs, a post hoc analysis to assess their impact on lorlatinib’s efficacy was performed. It showed that dose reductions in the first 16 weeks of treatment did not impact PFS or time to IC progression,” said Solomon.

“The systemic efficacy results, coupled with protection from IC progression and absence of new safety signals, indicate that first-line lorlatinib provides an unprecedented improvement in outcomes for patients with advanced ALK+ NSCLC,” summarized Solomon.