Abstract
Rearrangements of the anaplastic lymphoma kinase (ALK) gene are present in about 3% to 7% of patients with non–small cell lung cancer (NSCLC) and are the key drivers of cancer cell proliferation in ALK-positive NSCLC. ALK tyrosine kinase inhibitors (TKIs) are potent oral inhibitors of the abnormal ALK protein and are standard first-line treatments for patients with ALK-positive metastatic NSCLC (mNSCLC). Lorlatinib is a brain-penetrant, third-generation ALK TKI that was approved by the US Food and Drug Administration in 2018 for the second- or third-line treatment of patients with ALK-positive mNSCLC and in 2021 for first-line treatment, based on the results of the phase III CROWN study (NCT03052608). The recent 5-year results of the CROWN study showed that median progression-free survival had yet to be reached in the lorlatinib group, corresponding to the longest progression-free survival reported with any single-agent molecular targeted treatment in advanced NSCLC and all metastatic solid tumors (Solomon et al., 2024). These results, along with the extended intracranial efficacy and consistent safety profile of long-term lorlatinib treatment, are unprecedented in patients with ALK-positive mNSCLC. This Grand Rounds article summarizes the efficacy, safety, and tolerability of lorlatinib after 5 years and includes a fictional patient case to demonstrate how advanced practice providers contribute to personalized patient care and the identification and management of adverse events.
