Lorlatinib showed significant benefit in 1st line treatment of advanced ALK-positive non-small cell lung carcinoma

Lorlatinib – 3rd generation ALK inhibitor

Lorlatinib is a 3rd generation anaplastic lymphoma kinase (ALK) inhibitor. It has previously demonstrated antitumor efficacy in patients with ALK⁺ NSCLC who have progressed on crizotinib, alectinib, or ceritinib. It was specifically developed to inhibit mutations that lead to resistance to other ALK inhibitors and to penetrate well into the CNS.

Crizotinib is a 1st generation ALK inhibitor that was the standard of care in the 1st line treatment for this indication at the time the CROWN study was initiated.

CROWN Study

CROWN is an ongoing global randomized (1:1) phase III study comparing lorlatinib with crizotinib in 296 patients with advanced ALK⁺ NSCLC who had not previously received any treatment for metastatic disease.

The primary endpoint is progression-free survival (PFS) assessed by centrally blinded independent reviewers. Secondary endpoints include overall survival, other survival metrics, objective response rate (ORR), and intracranial response rate, also assessed independently. Results of an interim analysis, published at the end of last year, were done after achieving 75% of expected events, i.e., progression or death in the study population.

Interim Data Analysis Results

Efficacy

After 12 months, 78% of patients in the lorlatinib group and 39% in the crizotinib group were alive without disease progression (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.19–0.41; p < 0.001). The ORR was 76% with lorlatinib and 58% with crizotinib.

In patients with measurable brain metastases (n = 30), an intracranial response was achieved in 82% of the lorlatinib group compared to 23% of the crizotinib group, with complete intracranial remission (CR) observed in 71% of lorlatinib patients vs. 8% of crizotinib patients.

Safety

Adverse events observed in more than 20% of patients with lorlatinib included hypercholesterolemia (in 70%), hypertriglyceridemia (in 64%), edema (in 55%), weight gain (in 38%), peripheral neuropathy (in 34%), cognitive effects (in 21%), and diarrhea (in 21%). Grade 3/4 adverse events were reported in 72% of lorlatinib patients and 56% of crizotinib patients. For lorlatinib, the most common were hypertriglyceridemia (in 20% of patients), weight gain (in 17%), hypercholesterolemia (in 16%), and hypertension (in 10%). Permanent discontinuation due to adverse effects occurred in 7% of lorlatinib patients and 9% of crizotinib patients. No significant difference in quality of life changes was found between treatment groups, although numerically greater improvement was observed with lorlatinib.

Discussion and Conclusion

Lorlatinib has shown itself to be highly effective in the first line treatment of NSCLC, even intracranially, in the interim analysis of the CROWN study data. Data on overall survival of treated patients will be very important, but are not yet mature for analysis. The advantage of using lorlatinib in the 1st line is the potential to eliminate cell clones with resistant mutations from the start, which in the case of treatment with other ALK inhibitors would cause progression or treatment failure.

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Source: Shaw A. T., Bauer T. M., de Marinis F. et al.; CROWN Trial Investigators. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 2020 Nov 19; 383 (21): 2018−2029, doi: 10.1056/NEJMoa2027187.