Characterization and clinical management of adverse events following treatment with repotrectinib: a TRIDENT-1 analysis

Clinical Snapshot

Key Findings

• P Value: Not applicable (descriptive analysis)

• Effect Size: Median relative dose intensity 90%; dose modifications in 39% (interruption) and 38% (reduction)

• Primary Outcome: Most common treatment-related adverse events: dizziness (58%) and dysgeusia (50%)

• Nnt Or Sensitivity: 78% of patients with dizziness improved with dose modifications; 14% required permanent QD dosing

• Confidence Interval: Not reported

Clinical Application

Manageable adverse event profile with established mitigation strategies suitable for routine oncology practice Relevant for Australian oncologists managing targeted therapy patients; aligns with TGA-approved indications and PBS considerations for specialized cancer medications Patients with ROS1 fusion-positive NSCLC or NTRK fusion-positive solid tumors receiving repotrectinib

Abstract

BACKGROUND: Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. PATIENTS AND METHODS: The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. RESULTS: In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. CONCLUSION: Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.

References

1. 1.Drilon, A., Cho, B. C., Camidge, D. R., Nagasaka, M., Besse, B., Solomon, B., Goto, K., Wolf, J., Popat, S., Felip, E., Yang, N., de Langen, A. J., Lu, S., Velcheti, V., Lin, A. L., Calvet, C. Y., Li, L., Tschaika, M., Afsar, S., Yang, H., & Lin, J. J. (2026). Characterization and clinical management of adverse events following treatment with repotrectinib: a TRIDENT-1 analysis. The Oncologist. https://doi.org/10.1093/oncolo/oyag137