First-line Therapy Options for ALK+ NSCLC

Key Takeaways:

• Crizotinib had been standard in the treatment of anaplastic lymphoma kinase (ALK)+ disease; however, lack of central nervous system (CNS) penetration could lead to brain progression; next-generation tyrosine kinase inhibitors (TKIs), including alectinib, brigatinib, lorlatinib, and ceritinib, do penetrate CNS.

• After CNS penetration, choosing an ALK inhibitor is typically based on anticipated adverse events (AEs). 

This transcript has been edited for clarity.

ALK (anaplastic lymphoma kinase) non-small-cell lung cancer is sensitive to tyrosine kinase inhibitors. The historical standard was crizotinib. Despite being an effective drug, the major limitation with crizotinib was limited central nervous system (CNS) penetration. And, as a consequence, there was significant progression within the brain. This realization led to the development of newer tyrosine kinase inhibitors that had improved CNS penetrance with drugs such as alectinib, brigatinib, lorlatinib, and ceritinib. 

When we think about ALK-positive non-small-cell lung cancer, we have a variety of options now with next-generation tyrosine kinase inhibitors, all of which have CNS penetration. Alectinib was the first one to be reported, based off of the ALEX study.^[1] And, in this study, alectinib was compared to crizotinib in treatment-naïve ALK-positive non-small-cell lung cancer and showed a significant improvement in progression-free survival and, subsequently, overall survival when compared to crizotinib. Subsequent studies looking at brigatinib, per the ALTA-1L study, and lorlatinib, more recently, per the CROWN study, have shown similar results.^[2,3] 

So, when thinking about choosing ALK inhibitors, a key component is to think about the need for brain penetration and, more importantly, what are the differences in chronic adverse events between these drugs? With crizotinib, which has fallen out of favor as a standard of care option due to its limited CNS penetration, the standard side effects included vision issues, hepatotoxicity, edema, nausea, and diarrhea. More recently, with alectinib, we've seen that a lot of those issues are not present, though there are some unique side effects that are noticeable with alectinib that were not present with crizotinib, specifically hepatotoxicity and a photosensitivity rash. 

Brigatinib has a very well-tolerated profile as well but does have a very unique side effect of cough and early-onset pulmonary events. In most cases, these are reversible, but they do need to be monitored. Similar to alectinib, hepatotoxicity is an important side effect to monitor closely as is elevated creatine kinase. The ALK tyrosine kinase inhibitor with the most unique profile is lorlatinib. 

And lorlatinib was specifically designed for excellent CNS penetration. However, it also comes with some unique side effects, specifically elevated lipids—so, monitoring cholesterols and triglycerides are very important on therapy—hepatotoxicity, which is actually in common with alectinib and brigatinib. But the unique side effect of lorlatinib is neurotoxicity, and this is a dose-dependent phenomenon that patients typically report feeling cognitively slower, having difficulty thinking, and having foggy memory. And, for a drug that will be used chronically, this is an important side effect to consider when thinking about using ALK inhibitors in the first-line setting.