The CROWN study (ClinicalTrials.gov identifier NCT03052608) of lorlatinib, a brain-penetrant, third-generation ALK tyrosine kinase inhibitor, vs crizotinib, an inhibitor of receptor tyrosine kinases (including ALK), in the first-line treatment of patients with advanced ALK-positive non–small cell lung cancer (NSCLC) is an ongoing, international, randomized, open-label phase III trial being conducted in 104 centers across 23 countries. After 5 years of follow-up, data from the phase III study continue to show prolonged progression-free survival in patients who receive lorlatinib. Coupled with durable intracranial efficacy and the absence of new safety signals with lorlatinib, “these results indicate an unprecedented improvement in outcomes for patients with advanced ALK-positive NSCLC,” according to the study authors. These findings were presented by Benjamin J. Solomon, PhD, MBBS, and colleagues at the 2024 ASCO Annual Meeting (Abstract LBA8503).
Benjamin J. Solomon, PhD, MBBS
Study Methodology
Researchers randomly assigned 296 treatment-naive patients with advanced ALK-positive NSCLC 1:1 to receive lorlatinib at 100 mg daily (n = 149) or crizotinib at 250 mg twice daily (n = 147). In this post hoc analysis, the researchers presented their investigator-assessed efficacy outcomes, safety, and biomarker analyses. Formal statistical testing was not performed.
Results
As of October 31, 2023, 74 of 149 patients (50%) vs 7 of 142 patients (5%) were still receiving lorlatinib or crizotinib, respectively. With a median duration of follow-up for progression-free survival of 60.2 months (95% confidence interval [CI]) = 57.4–61.6 months) in the lorlatinib arm and 55.1 months (95% CI = 36.8–62.5 months) in the crizotinib arm, median progression-free survival was not reached (95% CI = 64.3 months to not reached) with lorlatinib and 9.1 months (95% CI = 7.4–10.9 months) with crizotinib (hazard ratio [HR] = 0.19, 95% CI = 0.13–0.27).
Five-year progression-free survival was 60% (95% CI = 51%–68%) with lorlatinib and 8% (95% CI = 3%–14%) with crizotinib. Median time to intracranial progression was not reached (95% CI = not reached to not reached) with lorlatinib and 16.4 months (95% CI = 12.7–21.9 months) with crizotinib (HR = 0.06, 95% CI = 0.03–0.12).
After 5 years of follow-up, the median progression-free survival in the lorlatinib arm has yet to be reached, corresponding to the longest progression-free ever reported in [patients with] advanced NSCLC.— Benjamin J. Solomon, PhD, MBBS, and colleagues
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In the patients without baseline brain metastases in the lorlatinib arm, only 4 of 114 developed brain progression occurring within the first 16 months of treatment. Grade 3 or 4 adverse events occurred in 77% of patients receiving lorlatinib and in 57% of patients receiving crizotinib. Treatment-related adverse events led to treatment discontinuation in 5% and 6% of patients in the lorlatinib and crizotinib arms, respectively. The safety profile of lorlatinib was consistent with that observed in prior analyses. Emerging new ALK mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment (n = 31).
Conclusions
“After 5 years of follow-up, the median progression-free survival in the lorlatinib arm has yet to be reached, corresponding to the longest progression-free ever reported in [patients with] advanced NSCLC. Coupled with prolonged intracranial efficacy and absence of new safety signals, these results indicate an unprecedented improvement in outcomes for patients with advanced ALK-positive NSCLC,” concluded the study authors.
Disclosure: Funding for this study was provided by Pfizer. For full disclosures of the study authors, visit coi.asco.org.
