Abstract 1361: Population pharmacokinetic modeling of avelumab to support flat dosing in patients with locally advanced or metastatic urothelial carcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-07, Vol.81 (13_Supplement), p.1361-1361
• Main Authors: Li, Jerry, Bello, Carlo, Khandelwal, Akash, Vugmeyster, Yulia, Nickens, Dana, Ruiz-Garcia, Ana, Lin, Swan
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2021-1361

BACKGROUND Avelumab is a human IgG1 monoclonal antibody targeting PD-L1 that is approved in the US for second-line locally advanced or metastatic urothelial carcinoma (UC) and first-line maintenance (1LM) treatment of patients with UC that has not progressed with first-line platinum-containing chemotherapy. The current analysis aimed to evaluate the pharmacokinetics (PK) of avelumab and justify an 800-mg every-2-week (Q2W) flat-dosing regimen for 1LM-UC patients. METHODS: PK data from avelumab-treated patients with solid tumors in 4 clinical studies were included. Patients received weight-based doses of avelumab ranging from 1 to 20 mg/kg, while all 1LM-UC patients received doses of 10 mg/kg. Blood samples from 1LM-UC patients were collected predose and immediately before the end of infusion from cycles 1 through 13 for evaluation of PK and immunogenicity. Avelumab population pharmacokinetics (popPK) were characterized using the structural component of a pre-established time-varying popPK model. Baseline clearance and percent change in clearance from baseline were explored through summary statistics to assess the potential effects of immunogenicity and PD-L1 status on avelumab PK. The distribution of single-dose and steady-state exposure metrics predicted in the 1LM-UC population were compared to simulated exposure distributions following 10-mg/kg Q2W and 800-mg Q2W avelumab monotherapy treatment to support the 800-mg Q2W flat-dosing regimen. PopPK analyses were performed with NONMEM version 7.4.3, and data manipulation and postprocessing were performed with R version 3.5.0. RESULTS: A 2-compartment popPK model with body weight as a covariate on clearance and volume satisfactorily characterized avelumab PK using 15,392 PK records from 2,171 patients, which included 4,566 PK records from 344 1LM-UC patients. Avelumab PK parameters in 1LM-UC patients were consistent with parameters in other patients with solid tumors. Average baseline clearance and percent change from baseline clearance in 1LM-UC patients grouped by immunogenicity (antidrug antibody ever positive vs never positive) or PD-L1 status (positive vs negative vs missing PD-L1 immune cell expression by SP263) ranged from 0.0257 to 0.0295 L/h and from −2.3% to 6.9%, respectively. The distributions of post hoc predicted single-dose and steady-state avelumab exposures overlapped with simulated exposures of patients with solid tumors receiving avelumab 800 mg Q2W. CONCLUSIONS: The popPK analysis found t