Bone-Directed Therapy and Comparing ROS1-Directed TKIs in ROS1-Positive Advanced Non-Small Cell Lung Cancer

Given the patient's osseous disease, the panel discusses bone-directed therapy integration. Dental clearance is required before initiation due to risk of osteonecrosis of the jaw. For symptomatic bone disease or high fracture risk, bone-directed agents are introduced early with calcium and vitamin D supplementation. For less symptomatic patients, a quarterly rather than monthly dosing cadence is preferred to reduce treatment burden. Palliative radiation remains an option for patients with inadequately controlled bone pain despite systemic therapy, particularly while awaiting biomarker results.

Recent data from ASCO support non-inferiority of every-3-month versus monthly dosing for bisphosphonates, and denosumab loading dose data further support extended interval dosing.

The panel then addresses how to counsel patients on differences between ROS1-directed TKIs. Lorlatinib is endorsed as the first choice based on clinical outcome data and tolerability. Crizotinib offers activity but limited CNS penetration. Entrectinib has CNS activity but CNS-related toxicities including dizziness are problematic for patients presenting with neurological symptoms. One panelist recounts a patient who developed acute neurological symptoms on entrectinib at a theme park, initially suspected as a stroke. Lorectinib (repotrectinib) has activity including against solvent-front resistance mutations but requires titrated dosing and carries neurological side effects that complicate use in patients already experiencing CNS symptoms. The panel stresses that starting patients on the best available agent upfront is the most important decision because later-line responses are consistently inferior to first-line outcomes.