Lorlatinib Approved for Metastatic ALK-Positive Non-Small Cell Lung Cancer

NSCLC cells.

The FDA has approved lorlatinib (Lorbrena®, Pfizer, Inc.) for the treatment of patients with anaplastic lymphoma kinase (ALK)–positive non-small cell lung cancer (NSCLC).

A subset of NSCLCs defined by their chromosomal rearrangements of the ALK gene are highly sensitive to small-molecule ALK tyrosine kinase inhibitors (TKIs). Lorlatinib is a novel third-generation small-molecule ALK TKI that was designed to cross the blood-brain barrier in an effort to better treat patients whose disease has progressed to the central nervous system, as this is a major cause of illness and death.

“The CROWN trial is a global randomized phase 3 trial comparing lorlatinib with crizotinib (the standard-of-care first-line treatment at the time of trial initiation) in patients with previously untreated advanced ALK-positive NSCLC,” reported Alice T. Shaw, MD, PhD, Paula O’Keeffe Endowed Chair in Thoracic Oncology at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School, and colleagues in their publication of results of the CROWN trial (NCT03052608), on which the approval was based, in the New England Journal of Medicine in November 2020. “In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib.”

CROWN enrolled 296 patients with ALK-positive NSCLC who had not received prior systemic treatment for metastatic disease. Eligible patients had at least one extracranial measurable target lesion that had not been previously irradiated. Patients were randomly assigned in a 1:1 ratio to receive either 100 mg lorlatinib daily or 250 mg crizotinib twice daily. The primary end point was progression-free survival, as assessed by a blinded independent review committee, or death from any cause. Secondary end points included overall survival, independently assessed objective response and intracranial response, and safety.

At 12 months, 78% of patients treated with lorlatinib were alive without disease progression, compared with 39% of patients treated with crizotinib. An objective response occurred in 76% of patients treated with lorlatinib versus 58% of patients treated with crizotinib. In patients with measurable brain metastases, the intracranial response rate was higher with lorlatinib (82% vs 23%), with an intracranial complete response rate of 71% among patients treated with lorlatinib.

“Among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival, a higher overall and intracranial response, and better quality of life than those who received crizotinib,” concluded Dr. Shaw and colleagues.

Adverse events occurring in at least 20% of patients receiving lorlatinib included hyperlipidemia, edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, and cough.

The recommended dose of lorlatinib for patients with ALK-positive NSCLC is 100 mg orally once daily.

For More Information

Shaw AT, Bauer TM, de Marinis F, et al (2020). First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Eng J Med, 383 (21):2018-2029. DOI:10.1056/NEJMoa2027187

Clinicaltrials.gov (2021). A study of lorlatinib versus crizotinib in first line treatment of patients with ALK-positive NSCLC. NLM identifier: NCT03052608.

Lorbrena®(lorlatinib) prescribing information (2021). Pfizer. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210868s004lbl.pdf

US Food & Drug Administration (2021). FDA approves lorlatinib for metastatic ALK-positive NSCLC. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-lorlatinib-metastatic-alk-positive-nsclc

Image credit: Ventana Medical Systems, Inc. Licensed under CC BY-SA 4.0

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