Dr Bestvina on the Management of AEs Associated With Repotrectinib in ROS1+ NSCLC

Christine Bestvina, MD, thoracic oncologist, assistant professor of medicine, Section of Hematology/Oncology, Department of Medicine, University of Chicago Medicine, discusses strategies for managing adverse effects (AEs) associated with the ROS1 TKI repotrectinib (Augtyro) in patients with ROS1-positive metastatic non–small cell lung cancer (NSCLC).

The FDA approved repotrectinib for patients with locally advanced or metastatic NSCLC harboring ROS1 fusions on November 15, 2023. The approval was supported by findings from the phase 1/2 TRIDENT-1 trial (NCT03093116). In the phase 2 dose-expansion cohorts, patients with ROS1-positive NSCLC experienced high response rates regardless of whether they were TKI naive or TKI pretreated.

Regarding safety, 33% of patients in TRIDENT-1 experienced serious AEs. Treatment-related dose interruptions, reductions, and discontinuations caused by AEs were required by 48%, 35% and 8% of patients, respectively. The most frequent AEs to occur in at least 10% of patients included dizziness (all grade, 63%; grade 3 or 4, 1.9%), dysgeusia (48%; 0%), peripheral neuropathy (47%; 1.9%), ataxia (28%; 0.4%), cognitive disorders (23%; 0.8%), headache (19%; 0%), constipation (36%; 0%), nausea (19%; 0.4%), diarrhea (13%; 0.4%), vomiting (10%; 0.8%), dyspnea (30%; 7%), cough (14%; 0%), fatigue (24%; 1.1%), edema (12%; 0.8%), muscular weakness (21%; 1.5%), myalgia (12%; 0.4%), increased weight (14%; 1.9%), and vision disorders (11%; 0%).

When considering treating patients for ROS1-positive disease with repotrectinib, it is important to be aware of the potential benefit of dose interruption, specifically in cases of dizziness, Bestvina begins. Instead of an immediate dose reduction, interrupting the dose according to the severity of dizziness may be a prudent initial approach, she states.

Additionally, Bestvina states that it is important to recognize that neuropathy associated with repotrectinib may manifest differently from conventional chemotherapy-induced neuropathy. Although distal extremity neuropathy is often observed, atypical presentations such as peri-oral neuropathy may also occur, which may be distinct from neuropathies commonly encountered in clinical practice. This highlights the importance of consistant monitoring for various neuropathic manifestations, Bestvina explains.

Employing dose interruption and reduction as a tool for toxicity management is crucial for optimizing the drug's accessibility to patients while ensuring their well-being, Bestvina emphasizes. Understanding and navigating these nuances in repotrectinib's toxicity profile allows for informed treatment decisions, tailored strategies, and optimized outcomes for patients receiving repotrectinib, she concludes.