Exposure-Response Analysis of Repotrectinib to Support the Dose Recommendation for Patients With ROS1-Positive NSCLC or NTRK-Positive Solid Tumors.

Abstract

To support the benefit-risk assessment and dose justification of repotrectinib for patients with c-ros oncogene 1 (ROS1) positive non-small cell lung cancer (NSCLC) or neurotrophin receptor tyrosine kinase (NTRK)-positive solid tumors, exposure-response analyses were conducted. The analysis used data from the TRIDENT-1 trial for key clinical efficacy endpoints-objective response rate (ORR) and progression-free survival (PFS), as well as 5 clinical safety endpoints: Grade 2 or higher (Gr2+) dizziness, Gr2+ anemia, Grade 3 or higher (Gr3+) treatment-emergent adverse events (AEs), Gr2+ neurologic AEs, and dose reduction or interruption due to AEs. The exposure-response relationship for ORR was characterized by logistic regression with average repotrectinib exposure over the first 56 days of dosing; PFS or safety endpoints were evaluated by Cox proportional-hazards models with time-varying cumulative half-daily average drug concentration. The model predicted efficacy and safety were compared for 160 mg QD/BID (160 mg QD for 14 days, followed by 160 mg BID) and 160 mg QD under different food statuses. The recommended dose of 160 mg QD/BID demonstrated improved ORR and PFS over 160 mg QD in both ROS1-positive NSCLC and NTRK-positive solid tumors, while the increase in AEs was minimal. Predicted efficacy and safety were comparable across food conditions, supporting the administration of 160 mg QD/BID regardless of food. This work highlighted the importance of selecting appropriate exposure measures in exposure-response analyses, particularly when dose or dose frequencies change throughout treatment. The integrated exposure-response analyses provided a robust framework to support the repotrectinib dosing strategy.