Approximately 3-7% of patients with advanced NSCLC harbor ALK-rearrangements, which render the tumor sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Thus, molecular testing at the time of diagnosis is key to identifying these patients. Crizotinib was the first-in-class TKI approved for use in ALK-positive NSCLC; however, its duration of clinical benefit is limited due to the development of acquired resistance that leads to disease progression and metastases, often in the brain. Second-generation TKIs, including ceritinib, alectinib, and brigatinib, have shown efficacy in patients whose disease has progressed on crizotinib and as first-line therapy, including in patients with brain metastases. Lorlatinib is a highly potent, brain-penetrant, third-generation ALK TKI, approved for the second- or third-line treatment of patients with ALK-positive NSCLC whose disease has progressed on first- and/or second-generation TKIs.

The open-label, randomized, multicenter, phase III CROWN trial compared the efficacy and safety of lorlatinib versus crizotinib as first-line treatment for patients with advanced ALK-positive NSCLC. Results from a planned interim analysis were presented during the first Presidential Symposium at ESMO’s 2020 virtual meeting by Dr Benjamin Solomon (Peter MacCallum Cancer Centre, Melbourne, Australia). The trial enrolled 296 patients who were randomized to receive either lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily). The primary endpoint was progression-free survival (PFS) by blinded independent central review and secondary endpoints included objective response rate (ORR), intracranial ORR (IC-ORR), overall survival (OS), safety, and quality of life (QoL). At a median follow-up of 18.3 months for lorlatinib and 14.8 months for crizotinib, the primary endopint was met, with lorlatinib treatment resulting in a statistically significant and clinically meaningful improvement in median PFS compared with crizotinib (not estimable [NE] versus 9.3 months; hazard ratio [HR], 0.28; P<0.001). At 12 months, the median PFS rate with lorlatinib was 78.1% versus 38.7% with crizotinib. The benefit of lorlatinib was consistent across all prespecified patient subgroups, including patients with brain metastases at baseline. ORR in the lorlatinib arm was significantly higher than in the crizotinib arm (76% versus 58%, respectively), and intracranial ORR in patients with measureable brain metastases was 82% with lorlatinib compared with 23% with crizotinib, with a complete response seen in 71% of patients versus 8%, respectively. The intracranial time to progression was significantly longer with lorlatinib compared with crizotinib, at NE versus 16.6 months (HR, 0.07; P<0.001). OS data were not mature at the time of the interim analysis; however, the HR for OS at this time point was 0.72 in favor of lorlatinib. The safety profile of lorlatinib was consistent with phase I/II data, with grade 3/4 AEs occurring in 72% of patients and 56% of patients treated with crizotinib. The most frequent AEs with lorlatinib were asymptomatic elevation of cholesterol and triglycerides. AEs leading to permanent treatment discontinuation occurred in 7% versus 9% of patients, respectively, and two deaths were reported as probably related to lorlatinib treatment. Of note, global QoL scores demonstrated a greater improvement from baseline in the lorlatinib arm versus the crizotinib arm (P<0.01), and these improvements were maintained over 18 treatment cycles.

Dr Solomon concluded that these results support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive NSCLC. He highlighted the remarkable intracranial efficacy of lorlatinib treatment that indicates not only a delay in progression of existing brain metastases but also a prevention of the development of new brain metastases. A discussant of the trial, Christine Lovly, MD (Vanderbilt Ingram Cancer Center, Nashville, Tennessee, US) acknowledged the promising efficacy shown with lorlatinib in the CROWN trial. However, she noted some unique side effects related to lorlatinib, including hypercholesterolemia, hypertriglyceridemia, and neurocognitive effects, and stressed the importance of considering survivorship issues related to the long-term use of TKIs, such as maintaining high QoL.

Reference

Solomon B, et al. Annals of Oncology 2020;31 (suppl; abstract LBA2)