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: Dose modifications resolved/downgraded dizziness in 78% of patients

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

• Nnt Or Sensitivity: 14% of patients unable to escalate to full BID dosing due to CNS adverse events

• Confidence Interval: Not reported

Clinical Application

Requires oncology expertise for dose modification and AE management, particularly neurological symptoms Relevant for TGA-approved indications; management strategies applicable within Australian oncology practice standards Australian 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.