Long-Term Safety and Management of Adverse Events Associated With Lorlatinib in ALK-Positive Metastatic NSCLC: A
Elizabeth A Krueger1, Elizabeth Castronovo2, Eunah Cho3
1From Massachusetts General Hospital, Boston, Massachusetts.
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.
Insights
Lorlatinib, an anaplastic lymphoma kinase (ALK) inhibitor, demonstrates unprecedented long-term efficacy and safety in advanced non-small cell lung cancer (NSCLC). Five-year results show sustained progression-free survival, offering new hope for ALK-positive NSCLC patients.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Anaplastic lymphoma kinase (ALK) gene rearrangements drive proliferation in 3-7% of non-small cell lung cancer (NSCLC) cases.
- ALK tyrosine kinase inhibitors (TKIs) are standard treatments for ALK-positive metastatic NSCLC (mNSCLC).
- Lorlatinib is a third-generation, brain-penetrant ALK TKI approved for various treatment lines.
Purpose of the Study:
- To summarize the 5-year efficacy, safety, and tolerability of lorlatinib in patients with ALK-positive mNSCLC.
- To highlight the role of advanced practice providers in personalized care and adverse event management for these patients.
Main Methods:
- Analysis of 5-year follow-up data from the phase III CROWN study (NCT03052608).
- Review of lorlatinib's efficacy, safety, and tolerability profile.
- Inclusion of a fictional patient case for illustrative purposes.
Main Results:
- Median progression-free survival (PFS) was not reached with lorlatinib, representing the longest PFS for any single-agent molecular targeted treatment in advanced NSCLC and metastatic solid tumors.
- Lorlatinib demonstrated extended intracranial efficacy.
- A consistent safety profile was observed with long-term lorlatinib treatment.
Conclusions:
- Five-year data confirm lorlatinib's unprecedented efficacy and sustained safety in ALK-positive mNSCLC.
- Lorlatinib offers a highly effective long-term treatment option for patients with advanced NSCLC harboring ALK rearrangements.
- Advanced practice providers play a crucial role in optimizing patient care and managing treatment-related adverse events.
