Emerging Strategies for Overcoming On/Off-Target Resistance in ALK-Positive NSCLC

Managing Lorlatinib Toxicity and Resistance Strategies

Lorlatinib's unique toxicity profile requires specialized management approaches, particularly for metabolic and neurocognitive effects. Weight gain, hyperlipidemia, and hypertriglyceridemia commonly occur, necessitating active monitoring and potential medication interventions. Neurocognitive toxicity, including memory, mood, and cognitive changes, represents a significant quality of life concern that often improves with dose modifications but requires careful patient counseling and monitoring.

Starting dose considerations may include initiating therapy at 75 mg rather than 100 mg for patients with psychiatric histories or increased risk of neurocognitive toxicity. Collaboration with specialized clinics, including weight management programs and consideration of GLP-1 agonists for significant weight gain, helps optimize patient outcomes. The development of institutional protocols for monitoring and managing these unique toxicities improves patient tolerance and treatment continuation.

Resistance mechanisms in ALK-positive disease include both on-target ALK mutations and off-target bypass pathways. Next-generation inhibitors like NVL-655 are designed to overcome acquired resistance mutations while sparing TRK to reduce neurocognitive toxicity. Combination strategies under investigation include MEK inhibition and other pathway targets, though the exceptional efficacy of first-line lorlatinib makes conducting randomized trials challenging due to extended follow-up requirements