medwireNews: First-line treatment with lorlatinib significantly improves progression-free survival (PFS), relative to crizotinib, in patients with advanced ALK-positive, non-small-cell lung cancer (NSCLC), results of the phase 3 CROWN study show.
Benjamin Solomon (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia), who presented the findings at the ESMO Virtual Congress 2020, told medwireNews that the take-home message from CROWN is that lorlatinib is “highly effective in controlling both disease systemically and also intracranially. And both areas are important.”
Benjamin Solomon highlights the key messages of the CROWN study and makes the case for using lorlatinib upfront in ALK-positive NSCLC (3:42)
He added that there are “compelling efficacy arguments provided by this study to use the lorlatinib as a first line option, in terms of getting effective control straight up, effective and durable control straight up, and preventing progression in the brain.”
For the study, treatment-naïve patients with ALK-positive stage IIIB or IV NSCLC were randomly assigned to receive the third-generation, ALK tyrosine kinase inhibitor lorlatinib 100 mg once daily (n=149) or crizotinib 250 mg twice daily (n=147).
After a median follow-up of 18.3 months in the lorlatinib arm and 14.8 months in the crizotinib arm, the researchers found that the risk for disease progression or death was a significant 72% lower with lorlatinib than with crizotinib.
More specifically, median PFS was not reached among the patients who received lorlatinib but was 9.3 months among those who received crizotinib, with estimated 12-month PFS rates at 78.1% and 38.7%, respectively.
Subgroup analyses revealed that the risk reductions in favor of lorlatinib appear to be greater for individuals with versus without brain metastases at baseline (hazard ratio [HR]=0.20 vs 0.32), for those of non-Asian versus Asian ethnicity (HR=0.19 vs 0.47), for patients younger than 65 years of age versus older (HR=0.22 vs 0.35), and for never smokers versus current smokers (HR=0.24 vs 0.36).
The objective response rate was higher in the lorlatinib group than in the crizotinib group, at 76% (3% complete and 73% partial responses) versus 58% (all partial responses), with median response durations not reached and 11.0 months, respectively.
The intracranial objective response rate was also higher with lorlatinib than with crizotinib, at 82% versus 23% for patients with measurable brain metastases at baseline and 66% versus 20% for those with measurable or nonmeasurable baseline brain metastases.
Furthermore, median time to intracranial progression was not reached among the patients who received lorlatinib but was 16.6 months among those who received crizotinib, resulting in a significant 93% lower risk for brain metastases with lorlatinib.
Median overall survival has not yet been reached in either arm, but at the time of analysis 15% of patients in the lorlatinib group and 19% of those in the crizotinib group had died.
Solomon noted that “the safety profile of lorlatinib was similar to that reported in previous studies.”
There were more grade 3 or 4 adverse events reported in the lorlatinib group than in the crizotinib group (72 vs 56%), but Solomon said that these were mainly laboratory abnormalities (hypercholesterolemia and hypertriglyceridemia) “that were asymptomatic and readily managed.”
He concluded that the findings “support the use of lorlatinib as an effective first-line therapy for patients with advanced ALK-positive NSCLC.”
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