Optimizing ROS1 Inhibitor Therapy in NSCLC
Key Points
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Four tyrosine kinase inhibitors (TKIs) are currently approved for ROS1 fusion-positive non-small cell lung cancer (NSCLC): crizotinib, entrectinib, repotrectinib, and taletrectinib.
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These agents share class-wide toxicities, including fatigue, nausea, diarrhea, edema, cardiotoxicity, hepatotoxicity, increased risk for skeletal fractures, hyperuricemia, and central nervous system (CNS) effects.
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Frequent follow-up visits are recommended for patients initiating ROS1 TKIs to enable timely dose adjustments and monitoring for serious side effects.
Managing ROS1 Inhibitor Toxicities
Estelamari Rodriguez, MD, MPH, of the University of Miami Health System, joined the cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss common adverse events and dose optimization strategies for the approved ROS1 TKIs in ROS1 fusion-positive NSCLC. The discussion covered crizotinib and entrectinib, first-generation TKIs, and repotrectinib and taletrectinib, second-generation TKIs.
Class-Wide Side Effects
Notable class-wide side effects associated with ROS1 TKIs include fatigue, diarrhea, edema, hepatotoxicity, pneumonitis, cardiotoxicity, skeletal fractures, hyperuricemia, and CNS effects such as dizziness. Physicians should monitor EKG and liver function tests in patients receiving any ROS1 inhibitor and counsel them on expected side effects. “I have patients, especially younger patients, that have never had CNS dizziness, and it can be very disturbing,” Dr. Rodriguez said.
Crizotinib and Entrectinib Dosing in NSCLC
Crizotinib primarily targets ALK and ROS1 mutations. The recommended dose for crizotinib is 250 mg twice daily, with dose reductions to 200 mg twice daily and then 250 mg once daily. The doctors noted that crizotinib has largely fallen out favor because of limited CNS activity and the availability of newer-generation TKIs.
Entrectinib also targets ROS1 and ALK, and additionally inhibits TRK. The starting dose is 600 mg once daily, with reductions to 400 mg and then 200 mg once daily. Like crizotinib, entrectinib is less appealing than newer-generation TKIs because it lacks CNS responses and does not prevent resistant mutations, Dr. Rodriguez said.
Repotrectinib Doses and Optimizations
Repotrectinib is a second-generation anti-ROS1 and anti-NTRK TKI. The recommended dose is 160 mg once daily for 14 days, followed by 160 mg twice daily. The recommended reduced doses are 120 mg and 80 mg, either once or twice daily based on the prior schedule. Data have shown that patients who require dose reductions still maintain effective responses.
As dizziness may raise concerns for brain metastases, Dr. Rodriguez suggested holding the drug to see if symptoms resolve before ordering a brain MRI. “Don’t be afraid to find the dose that is going to allow those patients to stay on treatment longer, because these [second-generation TKIs] are more effective agents and they can work at lower doses,” Dr. Rodriguez said.
Taletrectinib Expands the ROS1 Therapeutic Armamentarium
Taletrectinib is the most recently approved TKI for ROS1 fusion-positive NSCLC. The recommended starting dose is 600 mg once daily, with reductions to 400 mg once daily, then 200 mg once daily. Some patients may experience significant nausea or diarrhea, so physicians should discuss that possibility with them and prescribe antiemetics or antidiarrheals as needed. While CNS dizziness is reported as a common side effect of taletrectinib, it is not as pronounced as with other ROS1 TKIs, said Dr. Rodriguez.
“For most of these drugs, as we’re making adjustments, we are going to see patients sometimes weekly or monthly… After that, when we have found a dose that works for that patient, then we can see them less often, but, those first three months, these are TKIs that you need to talk to the patients, manage them, and make adjustments,” Dr. Rodriguez said.