Dr Gerber on the Neurocognitive Tradeoffs of Later-Generation ALK TKIs in NSCLC

“Thinking about these toxicities is a very different scenario than thinking about most other toxicities, because they can be so acutely harmful depending on the circumstances.”

David Gerber, MD, professor of internal medicine, the David Bruton Jr. Professor in Clinical Cancer Research, and codirector of Education and Training at UT Southwestern Medical Center’s Harold C. Simmons Comprehensive Cancer Center, reviewed the evolution of ALK TKIs and the central nervous system (CNS) toxicity tradeoffs seen with later-generation agents in non–small cell lung cancer (NSCLC), a topic covered in the Bridging the Gaps in Lung Cancer meeting.

Gerber walked through the 4 generations of ALK inhibitors, noting that first-generation crizotinib (Xalkori) was originally developed as a MET inhibitor before being repurposed once ALK-positive NSCLC was recognized as clinically relevant in 2007. Second-generation agents, including ceritinib (Zykadia), brigatinib (Alunbrig), alectinib (Alecensa), and entrectinib (Rozlytrek), improved upon crizotinib by targeting emerging gatekeeper resistance mutations and offering better CNS penetration, he explained. Third-generation lorlatinib (Lorbrena) builds on those advantages with even stronger CNS activity and targets a specific gatekeeper mutation, while fourth-generation agents, still investigational and not yet FDA approved, are designed to address combination resistance mutations involving more than one molecular change.

Gerber highlighted a key tradeoff with lorlatinib: in addition to targeting ALK, it also inhibits TRK, a mechanism that appears linked to superior CNS disease control across molecular subsets of lung cancer, but one that also carries a risk of serious neurocognitive toxicity, including changes in speech, memory, and behavior. He described real clinical experiences, including patients experiencing sleepwalking or dissociative episodes while driving, underscoring how acutely harmful these toxicities can be compared with more typical adverse effects.

Gerber said his hope is to find a way to achieve strong CNS disease control without this toxicity risk, or alternatively, to better identify in advance which patients are most likely to develop neurotoxicity so treatment can be tailored accordingly.