Model Informed Dosing Regimen and Phase I Results of the Anti‐PD‐1 Antibody Budigalimab (ABBV‐181)

Abstract

Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD‐1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body‐weight‐based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune‐related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD‐1 targeting agents. No treatment‐related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD‐1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure‐safety analyses did not indicate any trends. Observed PK and PD‐1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma

“…Budigalimab PK was approximately dose-proportional across the clinical doses evaluated. The two dosing regimens of 250 mg Q2W and 500 mg Q4W resulted in comparable dose-normalized exposures (supplementary Table 8) and maintained receptor saturation, as was previously predicted from population PK modeling and simulations and PK/PD assessments [14,15].…”

“…Budigalimab PK results from dose-escalation and dose-expansion cohorts, across varying doses and regimens, have been reported previously [ 14 , 15 ]. Budigalimab PK was approximately dose-proportional across the clinical doses evaluated.…”

“…The dose-escalation portion of the study followed a standard 3 + 3 design to determine the safety, maximum tolerated dose, and PK profile of budigalimab. On the basis of previously reported safety, PK, and PD data from the dose-escalation portion of the study [ 13 , 14 ], patients were then enrolled into two tumor-specific monotherapy dose-expansion cohorts, HNSCC and NSCLC, which are reported in this current analysis. Budigalimab was administered by intravenous infusion at either 250 mg Q2W or 500 mg Q4W until disease progression per RECIST v1.1 [ 16 ], confirmed disease progression per immune (i)RECIST [ 17 ], unacceptable toxicity, or other protocol-defined discontinuation criteria (supplementary Table 1).…”

“…Dose-finding and preliminary safety data from this first-in-human phase 1 study of budigalimab in patients with solid tumors (NCT03000257) have been previously presented [13]. The recommended phase 2 dose was determined to be 250 mg every 2 weeks (Q2W), 375 mg Q3W, or 500 mg Q4W, on the basis of pharmacokinetic (PK) modeling and simulations and PK/pharmacodynamic (PD) assessments that indicated these dosing regimens would lead to comparable exposure ranges and produce similar PD activity and a consistent toxicity profile [14,15]. This report describes safety, efficacy, biomarker, and PK data from the budigalimab monotherapy expansion HNSCC and NSCLC cohorts of study NCT03000257.…”

Integration of Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy into Model‐Informed Dose Selection in Oncology First‐in‐Human Study: A Case of Roblitinib (FGF401)

“…The benefit of using M&S to understand pharmacokinetic/pharmacodynamic (PK/PD) relationships during phase I has long been recognized 9–11 in all disease areas 12 . However, modeling‐related publications are generally based on phase II/III 13 or preclinical/translational studies, 14 with a limited number of examples in FIH oncology studies 15–18 …”