According to 5-year long-term follow-up data from the phase 3 CROWN study, the median progression-free survival (PFS) with lorlatinib, a brain-penetrant, third-generation ALK tyrosine kinase inhibitor (TKI) has yet to be reached among previously untreated patients with advanced ALK-positive non-small cell lung cancer (NSCLC). These results represent the longest PFS ever reported in advanced NSCLC.

These data will be presented by Benjamin Solomon, MBBS, PhD, Peter MacCallum Cancer Centre, Melbourne, Australia, at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

In the phase 3 CROWN study, 296 patients with advanced ALK-positive NSCLC who had not received previous treatment were randomized on a 1-to-1 basis to receive either lorlatinib (n = 149) or crizotinib (n = 147). Of all patients, 73 had baseline brain metastases. In this post hoc analysis, investigator-assessed efficacy outcomes and safety are reported. 

With a median follow-up duration o 60.2 months in the lorlatinib arm and 55.1 months in the crizotinib arm, the median PFS was not reached with lorlatinib and was 9.1 months with crizotinib (hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.13 to 0.27). The PFS rate at 5 years was 60% and 8%, respectively. The median time to intracranial progression was not reached in the lorlatinib arm and 16.4 months in the crizotinib arm (HR, 0.06; 95% CI, 0.03 to 0.12). 

Grade 3/4 adverse events occurred in 77% of patients with lorlatinib and 57% of crizotinib. In the lorlatinib arm, 5% of patients discontinued treatment due to treatment-related adverse events, vs 6% in the critotinib arm. The safety profile at this analysis was consistent with that observed at earlier analyses. 

Dr Solomon concluded, “The systemic efficacy results coupled with prolonged intracranial efficacy from first-line lorlatinib treatment indicate that this provides an unprecedented improvement in outcomes for patients advanced ALK-positive NSCLC.”

While David Spigel, MD, Sarah Canon Research Institute, Nashville, Tennessee noted, “it will be important to compare this treatment option to more commonly used ALK TKIs than crizotinib,” he noted, “These are the best results we have seen so far with the use of an ALK TKI in first-line treatment of patients with ALK-rearranged NSCLC…We have not seen anything close to this.”

Source:

Solomon BJ, Liu G, Felip E, et al. Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. Presented at the ASCO Annual Meeting. May 31 – June 4, 2024; Chicago, IL. Abstract #LBA8503