In an article in the Journal of Clinical Oncology, corresponding author Benjamin J. Solomon, MBBS, BS, PhD, of Peter MacCallum Cancer Centre, Melbourne, and colleagues provided a long-term analysis of 5-year outcomes from the phase III CROWN trial.1 Median progression-free survival had not been reached in patients receiving the third-generation tyrosine kinase inhibitor lorlatinib vs a median of 9.1 months in patients receiving the first-generation tyrosine kinase inhibitor crizotinib for previously untreated, advanced ALK-positive non–small cell lung cancer (NSCLC). The trial supported the March 2021 expanded approval of lorlatinib in this setting on the basis of improved progression-free survival and intracranial activity vs crizotinib and converted the 2018 accelerated approval to a regular approval in this setting.
Benjamin J. Solomon, MBBS, BS, PhD
Study Details
In this international open-label trial, 296 patients with ALK-positive NSCLC were randomly assigned to receive lorlatinib at 100 mg once daily (n = 149) or crizotinib at 250 mg twice daily (n = 147) in 28-day cycles. The current analysis presents 5-year outcomes.
Progression-Free Survival Among All Patients
At data cutoff for the current analysis (October 2023), median follow-up for progression-free survival was 60.2 months with lorlatinib and 55.1 months with crizotinib. Median progression-free survival was not reached (95% confidence interval [CI] = 64.3 months to not reached) in the lorlatinib group vs 9.1 months (95% CI = 7.4–10.9 months) in the crizotinib group (hazard ratio [HR] = 0.19, 95% CI = 0.13–0.27). Rates at 4 and 5 years were 63% vs 10% and 60% vs 8%, respectively.
Overall survival results were not yet mature. Circulating tumor DNA samples taken at the end of treatment were available for 31 patients in the lorlatinib group and 89 patients in the crizotinib group. Emerging new ALK resistance mutations were detected at the end of crizotinib treatment but not at the end of lorlatinib treatment.
Outcomes by Baseline Brain Metastasis Status
Among 35 vs 38 patients with measurable or nonmeasurable baseline brain metastases, median progression-free survival was not reached (95% CI = 32.9 months to not reached) with lorlatinib vs 6.0 months (95% CI = 3.7–7.6 months) with crizotinib (HR = 0.08, 95% CI = 0.04–0.19). The rate at 5 years was 53% with lorlatinib vs not evaluable with crizotinib, since all had experienced disease progression or died within 2 years.
Among patients without baseline brain metastasis, median progression-free survival was not reached (95% CI = 64.3 months to not reached) with lorlatinib vs 10.8 months (95% CI = 9.0–12.8 months) with crizotinib (HR = 0.24, 95% CI = 0.16–0.36). The rate at 5 years was 63% vs 10%, respectively.
Time to Intracranial Disease Progression
Among all patients, the median time to intracranial disease progression was not reached (95% CI = not reached to not reached) in the lorlatinib group vs 16.4 months (95% CI = 12.7–21.9 months) in the crizotinib group (HR = 0.06, 95% CI = 0.03–0.12). The likelihood of remaining free of intracranial disease progression at 5 years was 92% vs 21%, respectively.
Among patients with baseline brain metastases, the hazard ratio for the time to intracranial disease progression for lorlatinib vs crizotinib was 0.03 (95% CI = 0.01–0.13). At 5 years, the likelihood of being free of intracranial disease progression was 83% with lorlatinib and not evaluable with crizotinib, since all patients had experienced disease progression within 2 years. Among patients without baseline brain metastases, the hazard ratio for the time to disease progression for lorlatinib vs crizotinib was 0.05 (95% CI = 0.02–0.13). The likelihood of being free of disease progression at 5 years was 96% vs 27%, respectively.
Safety Profile
The median duration of treatment was 57.0 months with lorlatinib and 9.6 months with crizotinib.
Overall, grade 3 or 4 adverse events occurred in 77% of the lorlatinib group vs 57% of the crizotinib group; those occurring more frequently in the lorlatinib group included hypertriglyceridemia (25% vs 0%), hypercholesterolemia (21% vs 0%), weight gain (23% vs 2%), and hypertension (12% vs 1%). At 5 years, any-grade cardiovascular adverse events occurred in 28% of each group. Central nervous system adverse events were reported in 42% of the lorlatinib group; 86% were grade 1 or 2. Serious adverse events occurred in 44% vs 32% of patients. Adverse events led to discontinuation of treatment in 11% of patients in each group. Treatment-related death was reported in two patients in the lorlatinib group, as a result of cardiac failure and respiratory failure.
The investigators concluded: “After 5 years of follow-up, median [progression-free survival] has yet to be reached in the lorlatinib group, corresponding to the longest [progression-free survival] ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.”
DISCLOSURE: The study was supported by Pfizer. Dr. Solomon has received honoraria from AstraZeneca and Roche/Genentech; institutional honoraria from Merck Sharp & Dohme, Pfizer, and Amgen; and has served as a consultant or advisor to Merck Sharp & Dohme, Amgen, Lilly, BeiGene, Takeda, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Pfizer, Roche/Genentech, and Janssen. For full disclosures of the other study authors, visit ascopubs.org.
REFERENCE
1. Solomon BJ, Liu G, Felip E, et al: Lorlatinib versus crizotinib in patients with advanced ALK-positive non–small cell lung cancer: 5-Year outcomes from the phase III CROWN study. J Clin Oncol. May 31, 2024 (early release online).
