Comparative analysis of PD-1 target engagement of dostarlimab and pembrolizumab in advanced solid tumors using ex vivo IL-2 stimulation data

Dostarlimab (JEMPERLI) is an anti-programmed cell death protein-1 (PD-1) monoclonal antibody (mAb) which is approved by the US Food and Drug Administration for patients with recurrent/advanced mismatch repair-deficient solid tumors, including endometrial cancer, following progression on prior treatment, with approval based on data from the phase I GARNET trial. To support dostarlimab dose regimen recommendations, we estimated and compared the potency of dostarlimab relative to anti-PD-1 mAb pembrolizumab using both data published from the KEYNOTE-001 trial of pembrolizumab and data from the GARNET trial. PD-1 target engagement was assessed ex vivo in blood samples via a super antigen staphylococcal enterotoxin B stimulation assay and interleukin-2 (IL-2) stimulation ratios calculated for dostarlimab. A non-linear mixed-effect sigmoid maximum effect inhibitory model was fitted to dostarlimab IL-2 stimulation ratios using extracted pembrolizumab data as informative priors. The estimated half-maximal effective concentration was 1.95 mu g ml(-1) (95% credibility interval: 0.21-5.87) for dostarlimab and 1.59 mu g ml(-1) (95% confidence interval: 0.42-6.12) for pembrolizumab. These findings suggest dostarlimab and pembrolizumab to be equipotent for peripheral PD-1 suppression based on analysis of ex vivo IL-2 stimulation ratios. Accounting for a three-fold dilution between serum and tumor, a target dostarlimab trough concentration of similar to 54 mu g ml(-1) would be needed for 90% suppression in the tumor. These data support the use of dostarlimab as a potent PD-1 suppressor and the recommended dostarlimab monotherapy dose regimen of 500 mg Q3W x4 cycles followed by 1000 mg Q6W thereafter in recurrent/advanced solid tumors.