Population Pharmacokinetics and Exposure‐Response Analyses to Support Cofetuzumab Pelidotin ( ABBV ‐647) Dose Optimization in Non‐Small Cell Lung Cancer Patients

Cofetuzumab pelidotin (Cofe‐P) is an anti‐protein tyrosine kinase 7 (PTK7) antibody‐drug conjugate (ADC) being investigated for the treatment of adults with PTK7‐expressing, recurrent non‐small cell lung cancer (NSCLC). The first‐in‐human (FIH) trial demonstrated tolerability of dosages ≤ 2.8 mg/kg once every 3 weeks (Q3W) and ≤ 3.2 mg/kg Q2W. Population pharmacokinetics (popPK) and exposure‐response analyses were conducted to characterize Cofe‐P and unconjugated auristatin (Aur0101) payload pharmacokinetics and exposure‐efficacy (objective response rate (ORR)) and exposure‐safety (Grade ≥ 3 neutropenia, Grade ≥ 2 peripheral neuropathy or rash) endpoints to inform the selection of dosages for optimization. Data from the FIH (0.2–3.7 mg/kg Q3W, 2.1–3.2 mg/kg Q2W) and Phase 1b (2.8 mg/kg Q3W) studies were used for popPK and exposure‐response analyses. PopPK models adequately described pharmacokinetic data. Exposure‐response analyses showed that higher Cofe‐P (ADC) exposures increased the probability of achieving an objective response but also the occurrence of examined adverse events, particularly Grade ≥ 3 neutropenia. In non‐squamous epidermal growth factor receptor wild‐type NSCLC patients (≥ 90% with PTK7 2+ staining), analyses predicted that 3.2 mg/kg vs. 2.8 mg/kg Q3W dosing led to a higher ORR (35% vs. 21%) while maintaining a manageable safety profile (Grade ≥ 3 neutropenia: ≤ 39%). Predicted ORR and Grade ≥ 3 neutropenia are improvements over the standard‐of‐care, docetaxel. Dosing regimens < 2.4 mg/kg were not predicted to improve efficacy. Mean relative dose intensity was ≥ 86% across all Cofe‐P doses and schedules tested. Together, popPK and exposure‐response analyses support optimal dosing regimens of 2.4, 2.8, and 3.2 mg/kg Cofe‐P Q3W in patients with NSCLC.