Population Pharmacokinetic Modeling and Exposure–Response Assessment for the Antibody‐Drug Conjugate Brentuximab Vedotin in Hodgkin's Lymphoma in the Phase III ECHELON‐1 Study

The efficacy of the CD 30‐directed antibody‐drug conjugate ( ADC ) brentuximab vedotin was established in combination with chemotherapy as frontline treatment for advanced classical Hodgkin's lymphoma in the randomized phase III ECHELON ‐1 study. Population pharmacokinetic ( PK ) and exposure–response models were developed to quantify sources of PK variability and relationships between exposure and safety/efficacy end points in ECHELON ‐1. The influence of patient‐specific factors on the PK of the ADC and the microtubule‐disrupting payload monomethyl auristatin E ( MMAE ) was investigated; none of the significant covariates had a clinically relevant impact. Exposure–response analyses evaluated relationships between time‐averaged area under the curve ( AUC ; ADC , MMAE ) and efficacy end points ( ADC ) or safety parameters ( ADC , MMAE ). Exposure–efficacy analyses supported consistent treatment benefit with brentuximab vedotin across observed exposure ranges. Exposure‐safety analyses supported the recommended brentuximab vedotin starting dose (1.2 mg/kg every 2 weeks), and effective management of peripheral neuropathy and neutropenia with dose modification/reduction and febrile neutropenia with granulocyte colony‐stimulating factor primary prophylaxis.