Dr Saxena on the Evolving Utility of Targeted Therapies for ALK+ NSCLC

“[Findings] have shown a tremendous amount of disease control with these targeted therapies, particularly with the drugs that are targeting the ALK mutations.”

Ashish Saxena, MD, PhD, a medical oncologist and assistant professor of medicine at Weill Cornell Medicine, discussed the therapeutic relevance and evolving utility of targeted therapies for ALK-positive non–small cell lung cancer (NSCLC), particularly in the context of emerging survival data with next-generation ALK inhibitors.

Currently, four ALK TKIs are FDA approved for the treatment of advanced ALK-rearranged non–small cell lung cancer (NSCLC): alectinib (Alecensa), brigatinib (Alunbrig), ceritinib (Zykadia), and lorlatinib (Lorbrena). Alectinib, brigatinib, and ceritinib are considered second-generation agents, whereas lorlatinib is a third-generation ALK inhibitor. These therapies were developed to overcome resistance mechanisms and improve central nervous system (CNS) penetration compared with the first-generation ALK inhibitor crizotinib (Xalkori).

According to Saxena, lorlatinib has shown the most robust long-term efficacy data to date. In the phase 3 CROWN trial (NCT03052608), lorlatinib was compared with crizotinib in treatment-naive patients with advanced ALK-positive NSCLC. In the most recent analysis, the median progression-free survival (PFS) with lorlatinib had not yet been reached after 5 years of follow-up, highlighting durable disease control in this metastatic population. Notably, in patients without baseline brain metastases, 96% of those treated with lorlatinib remained free of CNS progression 5 five years.

Saxena noted that these outcomes are particularly compelling given the stage IV status of enrolled patients and emphasized the importance of CNS protection in this setting, as brain metastases remain a common site of progression in ALK-positive NSCLC.

The rationale for incorporating next-generation ALK inhibitors into frontline treatment reflects a broader shift toward prolonged disease control and improved quality of life. While earlier-generation inhibitors improved upon crizotinib in head-to-head trials, lorlatinib’s high intracranial efficacy and sustained systemic disease control make it a favorable first-line option in many clinical scenarios.

Saxena concluded that future directions include optimizing sequencing strategies and addressing resistance mechanisms that arise after lorlatinib. Ongoing research will continue to define the role of ALK inhibitors across treatment lines and determine whether alternative or combination approaches can further extend survival in this genetically defined subgroup of patients with ALK-positive NSCLC.