Comparative analysis of programmed cell death protein-1 (PD-1) target engagement of dostarlimab and pembrolizumab (pembro) in patients with advanced solid tumors using ex vivo interleukin 2 (IL-2) stimulation data
Objectives: Dostarlimab (JEMPERLI) is a novel anti-PD1 monoclonal antibody (mAb) indicated for patients with recurrent/advanced mismatch repair-deficient endometrial cancer. Dostarlimab is being investigated as monotherapy in the ongoing multicenter open-label, Phase 1 GARNET (NCT02715284) study in patients with recurrent/advanced solid tumors. The objective was to estimate and compare the potency of dostarlimab and the anti-PD-1 mAb pembro based on IL-2 stimulation ratio, to establish dostarlimab monotherapy dose recommendations.
Methods: PD-1 target engagement in blood samples is measured via a super antigen staphylococcal enterotoxin B stimulation assay. The ratio is calculated as the IL-2 concentration in the aliquot with spiked anti-PD-1 mAb over that in the aliquot with spiked IgG4 control. IL-2 stimulation data were available for dostarlimab from the GARNET study and for pembro from digitized data from the KEYNOTE-001 advanced solid tumor study (NCT01295827; ref 1).
First, an Emax model was fitted to digitized IL-2 patient-level data from KEYNOTE-001, collected across pembro doses of 0.005 to 10 mg/kg (ref 2), to determine the parameters describing the relationship (potency).
Dostarlimab IL-2 stimulation data from GARNET were fitted to the Emax model using the pembro data as Bayesian priors. In GARNET, samples were collected at baseline, cycle 1 day 3 (C1D3), C1D5, C1D15, C1D22, C1D29 (1000 mg only), and C2D1; and across dostarlimab doses of 1, 3, and 10 mg/kg every 2 weeks (Q2W), 500 mg Q3W, and 1000 mg Q6W. Dostarlimab exposures were measured in the same samples.
Results: Estimated EC50 of dostarlimab and pembro for inhibition of IL-2 stimulation were 1.95 µg/mL (95% credibility interval, 0.21–5.87) and 1.59 µg/mL (95% confidence interval, 0.42–6.12), respectively. Analysis of the ex vivo IL-2 stimulation ratio found dostarlimab and pembro to be equipotent for peripheral PD-1 suppression. Based on this analysis, target trough dostarlimab levels considered desirable to maintain 90% of maximal PD-1 suppression were >18 µg/mL in peripheral blood and >54 µg/mL in tissue/tumor (assuming a 3-fold dilution for typical mAbs [ref 3]). Doses of 500 mg Q3W (C1D22 median Ctrough: 44.3 µg/mL) and 1000 mg Q6W (C1D43 median Ctrough: 53.2 µg/mL) maintained exposures expected to result in maximal peripheral PD-1 suppression and likely to maintain required threshold trough levels throughout the dosing interval.
Conclusions: Both dostarlimab and pembro were found to be equipotent for peripheral PD-1 suppression. Dostarlimab was predicted to provide full peripheral inhibition throughout the dosing cycle. This analysis, combined with efficacy, safety, and population pharmacokinetic and exposure-response analyses (ref 4), supports a recommended dose schedule for dostarlimab monotherapy of 500 mg Q3W x4 followed by 1000 mg Q6W in recurrent/advanced solid tumors.
References: 1. Patnaik et al. Clin Cancer Res 2015;21:4286–93. 2. Elassaiss-Schaap et al. CPT Pharmacometrics Syst Pharmacol 2017;6:21–8. 3. Shah et al. J Pharmacokinet Pharmacodyn 2012;39:67–86. 4. Melhem et al. VirtualAcoP12, Nov 2021.
Funding: GSK (study 4010-01-001). Medical writing support was provided by Fishawack Indicia, part of Fishawack Health, funded by GSK.
Author(s)
- Daren Austin, GlaxoSmithKline (GSK), Brentford, UK (Presenting Author)
- Murad Melham, GlaxoSmithKline (GSK), Waltham, MA, USA (CoAuthor)
- Yash Gandhi, GSK, Collegeville, PA, USA (CoAuthor)
- Sharon Lu, GlaxoSmithKline (GSK), Waltham, MA, USA (CoAuthor)
- Sandra Visser, GSK, Collegeville, PA, USA (CoAuthor)