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.