First-line treatment with lorlatinib demonstrates long-term survival benefits in patients with advanced anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC), as shown in the 7-year update from the phase III CROWN study.
Specifically, patients who do not progress within 24 months while on lorlatinib have a low risk of progression or death at year 7 and may continue treatment for a longer period.
“Lorlatinib as a single agent is able to persistently control the disease, both systemically and intracranially, over the entire duration of treatment and may help shift advanced ALK-positive NSCLC toward a more chronic disease trajectory for a substantial fraction of patients,” the investigators said.
A total of 196 treatment-naïve patient with advanced ALK-positive NSCLC were randomized to receive either lorlatinib 100 mg once daily (n=149) or crizotinib 250 mg twice daily (n=147). A post hoc analysis was conducted to assess efficacy, safety, and biomarkers.
The median progression-free survival (PFS) was not reached (NR) with lorlatinib (95 percent confidence interval [CI], 68.5‒NR) and 9.1 months (95 percent CI, 7.4‒10.9) with crizotinib over a median follow-up of 83.0 and 77.2 months, respectively (hazard ratio [HR], 0.19, 95 percent CI, 0.13‒0.26). At 7 years, the PFS was 55 percent with lorlatinib and 3 percent with crizotinib. [Ann Oncol 2026;37:1242-1252]
In the lorlatinib group, patients without disease progression at the end of 24 months were 79-percent more likely to survive with no progression at 7 years.
New intracranial progression events did not occur after the first 30 months of lorlatinib treatment. The median time to intracranial progression was NR (95 percent CI, NR‒NR) with lorlatinib and 16.4 months (95 percent CI, 12.7‒21.9) with crizotinib (HR, 0.06, 95 percent CI, 0.03‒012).
“Overall survival follow-up is ongoing,” the investigators said. “[T]he number of events for a protocol-specified analysis has not been met.”
Safety
The safety profile of lorlatinib was consistent with that in the primary analysis of CROWN and in follow-up analyses. No new safety signals were detected, indicating no cumulative toxicity, with additional follow-up. [N Engl J Med 2020;383:2018-2029; Lancet Respir Med 2023;11:354-366]
Grade 3/4 adverse events (AEs) in the lorlatinib group were primarily driven by an increase in lipid values. After 7 years of follow-up, the incidence of cardiovascular AEs was lower with lorlatinib than crizotinib in patients with hyperlipidaemia despite a higher hyperlipidaemia incidence with lorlatinib.
Treatment-related discontinuations were similar between the two groups, and most discontinuations occurred within the first 2 years of lorlatinib use.
“CROWN 7-year findings underscore that the therapeutic benefits of lorlatinib substantially outweigh the potential risks associated with treatment-related AEs, reinforcing its value as a preferred first-line option,” the investigators said.
Resistance mechanism
Furthermore, the investigators found more genetic alterations in circulating tumour DNA samples from early progressors than in long-term responders on lorlatinib. They also identified new potential resistance mechanisms.
“Consistent with earlier analysis, EOT ctDNA samples … indicated that lorlatinib was able to suppress emergence of new ALK mutations,” the investigators said. “[I]nstead, gain of a few mutations in genes including FLT1/VEGFR1 and HDAC6, not reported before, were observed and may be associated with resistance mechanisms in some patients who developed disease progression on lorlatinib.”
Early progressors were found to have more genetic alterations and higher blood-based tumour mutational burden than the long-term responders. This finding suggests the possibility that increased complexity and tumour heterogeneity at baseline may modulate dependency on ALK, according to the investigators.