Pharmacokinetic profile and receptor occupancy of avelumab (MSB0010718C), an anti-PD-L1 monoclonal antibody, in a phase I, open-label, dose escalation trial in patients with advanced solid tumors.

3055 Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. Reported here is the pharmacokinetic (PK) profile of avelumab and receptor occupancy (RO) from a phase I dose escalation trial (NCT01772004). Previous in vitro experiments spiking anti-PD-L1 into human whole blood samples from healthy donors confirmed that 1 mcg/mL was sufficient for > 95% RO. Methods: In this study, dose escalation (3+3 design) was performed for 4 dose levels (DL 1, 3, 10, and 20 mg/kg). The dose limiting toxicity (DLT) evaluation period was 3 weeks. After DL safety was determined, accrual of additional patients (pts) was allowed for the purpose of generating additional safety, PK, and RO data. Results: 50 pts with advanced solid tumors were enrolled and treated with avelumab, Q2W. 4, 13, 13, and 20 pts were accrued to DL 1-4, respectively. Median pt age was 59 yrs (range 29-77); 19 had an ECOG PS of 0 and 29 had an ECOG PS of 1 (2 unknown).The median number of prior lines of therapy was 3 (range 1- ≥ 4). Data from 45 pts were evaluable for PK analysis. Cmaxand AUC increased linearly with dose. Half-lives were 66, 86, 92, and 115 h for DL 1, 2, 3 and 4, respectively, with no statistically significant differences between the 3 higher DLs. Trough levels at 10 mg/kg, but not at 1 and 3 mg/kg, were sufficient for > 95% RO at all dosing occasions. Population PK analysis showed that a 2-compartment model with linear elimination best described the data. Covariate analysis did not demonstrate significant correlation between body-size metrics and clearance. There was no significant change in absolute lymphocyte count or in additional multiple immune cell subsets evaluated. Conclusions: The PK and RO data indicate the 10 mg/kg dose of avelumab achieves excellent RO with a predictable PK profile. Based on these data and the safety profile reported separately, the 10 mg/kg dose is being tested in ongoing phase II trials. *Proposed INN. Clinical trial information: NCT01772004.