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.