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

Abstract 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 that avelumab PK in the 1LM-UC patient population is consistent with the previously described disposition. Neither immunogenicity nor PD-L1 status had clinically meaningful impacts on avelumab clearance, and no clinically meaningful change in avelumab clearance over time was detected. Overall, the popPK analysis supports the 800-mg Q2W flat-dosing regimen for 1LM-UC patients. Citation Format: Jerry Li, Carlo Bello, Akash Khandelwal, Yulia Vugmeyster, Dana Nickens, Ana Ruiz-Garcia, Swan Lin. Population pharmacokinetic modeling of avelumab to support flat dosing in patients with locally advanced or metastatic urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1361.