Pharmacokinetics (PK) of Tiragolumab in First‐in‐Human Study in Patients with Mixed Solid Tumors (GO30103)

Abstract

Tiragolumab is a first‐in‐class, fully human IgG1/kappa anti‐TIGIT monoclonal antibody that blocks binding of TIGIT to CD155 (the poliovirus receptor). We summarize PK data from the phase 1a/1b GO30103 study of every 3 weeks (Q3W) sequential dosing of tiragolumab (2, 8, 30, 100, 400, 600, or 1200 mg) followed by atezolizumab (1200 mg), every 4 weeks (Q4W) sequential dosing (tiragolumab 840 mg followed by atezolizumab 1680 mg) and Q4W co‐infusion (tiragolumab 840 mg plus atezolizumab 1680 mg). Serum samples were collected at multiple timepoints following tiragolumab and atezolizumab intravenous infusion in patients with solid tumors for PK and immunogenicity assessment. The serum PK profile of tiragolumab appeared biphasic with a rapid distribution followed by a slower elimination phase when administered alone or in combination with atezolizumab. In phase 1a, across tiragolumab 2–1200 mg (cycle 1), geometric mean (GM); coefficient of variation (CV%) serum tiragolumab Cmax ranged from 0.682–270 μg/mL (18.6%, 36.5%) and Cmin ranged from 0.0125–75.3 μg/mL (0.0%, 24.2%). GM systemic exposure (AUC0–21) ranged from 310–2670 μg day/mL (20.5%, 27.0%); inter‐individual variability in AUC0–21 ranged from 20.5–43.9%. Tiragolumab exposure increased in an approximately dose‐proportional manner when administered alone or with atezolizumab at doses ≥100 mg. Post‐baseline, 4/207 patients (1.9%) were positive for treatment‐emergent ADAs against tiragolumab, each at a single timepoint. Tiragolumab combined with atezolizumab demonstrated desirable PK properties, with no drug‐drug interaction or immunogenicity liability. There were no meaningful differences in tiragolumab or atezolizumab exposure between the Q4W co‐infusion and sequential dosing cohorts.ClinicalTrials.gov: NCT02794571 (date of registration June 6, 2016)This article is protected by copyright. All rights reserved

Implementation of a Three-Way Comparability Assessment for a Bioanalytical Anti-Drug Antibody Method

“…For this comparability assessment, we used incurred samples from a phase 1b tiragolumab study (12,13) to evaluate comparability in three bioanalytical laboratories. Given the low number of ADA+ samples in the phase 1b study, we selected 50 samples that screened positive, including six samples that were confirmed positive, and 50 samples that screened negative for our comparison.…”

“…After validation was completed in the three laboratories, comparability datasets were generated using 100 incurred samples from patients dosed with tiragolumab from a phase 1b study (12,13). BioA Lab 1 originally performed the clinical sample testing for these samples.…”

“…Each laboratory applied the same plate acceptance criteria set for study phase bioanalysis to generate their comparability dataset. The few ADA+ samples reported in the clinical study (six positives) all had low titers (four with a titer of < 1.3, one with titer of 1.34, and one with a titer of 2.28) (13); therefore, a titer comparison was not included in the analysis.…”