Population pharmacokinetics and exposure–response of anti‐programmed cell death protein‐1 monoclonal antibody dostarlimab in advanced solid tumours

Abstract

Aim: Develop a population pharmacokinetic (PopPK) model to characterise the pharmacokinetics (PK) of anti-programmed cell death protein-1 (PD-1) antibody dostarlimab, identify covariates of clinical relevance, and investigate efficacy/safety exposure-response (ER) relationships.Methods: A PopPK model was developed using Phase 1 GARNET (NCT02715284) trial data for dostarlimab (1, 3 or 10 mg kg À1 every 2 wk; 500 mg every 3 wk or 1000 mg every 6 wk; 500 mg every 3 wk  4 then 1000 mg every 6 wk [recommended regimen]) serum concentrations over time. Concentration-time data were analysed using nonlinear mixed effects modelling with standard stepwise covariate modelling. ER was explored for treatment-related adverse events and overall response rate (ORR) using logistic regression. Results: PopPK model/adverse event ER analyses included 546 patients (ORR ER analysis n = 362). Dostarlimab PK was well described by a 2-compartment model with time-dependent linear elimination. Time-dependent clearance decreased over time to a maximum of 14.9%. At steady state, estimated dostarlimab geometric mean coefficient of variation % clearance was 0.179 (30.2%) L d À1 ; volume of distribution was 5.3 (14.2%) L; terminal elimination half-life was 23.5 (22.4%) days. Statistically significant covariates were age, body weight, sex, time-varying albumin and alanine aminotransferase for clearance; body weight, albumin and sex for volume of distribution of the central compartment. Hepatic or renal impairment did not affect PK. There were no clinically significant ER relationships. Conclusion: Dostarlimab PK parameters are similar to other anti-programmed cell death protein-1 antibodies. The clinical impact of covariates on exposure was limitedto-moderate, supporting recommended dostarlimab monotherapy therapeutic dosing. K E Y W O R D S clinical pharmacology (drug safety), oncology (anticancer drugs), pharmacokinetics, therapeutics The GARNET trial does not have a designated study PI.

Dostarlimab: A Review

“…Noticeable, there is a correlation between tumor mutational burden status (TMBST) and dMMR/MSI status in some tumor types, including EC and colorectal cancer, and multivariate logistic regression analysis revealed that the impact of TMBST on overall response rate (ORR) was significant for the entire dataset and the EC subgroup. A similar correlation between TMBST and ORR has previously been reported for immune-checkpoint inhibitors [ 15 ]. There are no known drug–drug interactions with Dostarlimab, as it is a monoclonal antibody and thus is not a cytochrome P450 or drug transporter substrate, and is unlikely to be a cytokine modulator [ 18 ].…”

“…There are no data regarding overdose with Dostarlimab. Symptoms of overdosage are likely to be consistent with the adverse effect profile of Dostarlimab and may therefore involve significant immune-mediated reactions [ 14 , 15 ].…”

“…Using data from the GARNET trial the PK and exposure-response (ER) studies of Dostarlimab in patients with recurrent/advanced solid tumors were described. One of the goals was to identify clinically important variables and assess ER correlations for overall response rate (ORR) and the occurrence of relevant adverse events (AEs) [ 15 , 17 ].…”

Population pharmacokinetic models of anti-PD-1 mAbs in patients with multiple tumor types: A systematic review

“…Using the NIH study quality assessment tool, fourteen analyses had a good quality rating. Table 1 summarizes the characteristics of the included analyses, among which seven referred to nivolumab ( 21 , 22 , 28 – 32 ), four referred to pembrolizumab ( 20 , 23 , 33 , 34 ), one referred to cemiplimab ( 35 ), one referred to camrelizumab ( 36 ), and one referred to dostarlimab ( 37 ). The median (range) number of patients used to develop the PPK model was 1,137 (122–6,848) in fourteen analyses, with eight analyses (nivolumab 6/7, pembrolizumab 2/4) ( 21 , 28 – 34 ) involving more than 1,000 subjects.…”

“…The median (range) number of patients used to develop the PPK model was 1,137 (122–6,848) in fourteen analyses, with eight analyses (nivolumab 6/7, pembrolizumab 2/4) ( 21 , 28 – 34 ) involving more than 1,000 subjects. The data sources of twelve analyses were gathered from different clinical trials (nivolumab 6/7, pembrolizumab 3/4, cemiplimab 1/1, camrelizumab 1/1, and dostarlimab 1/1) ( 20 , 21 , 28 – 37 ), and two analyses were prospectively collected from a real-life patient cohort (nivolumab 1/7, pembrolizumab 1/4) ( 22 , 23 ). All fourteen analyses used internal evaluation to assess the model, of which nine analyses (nivolumab 4/7, pembrolizumab 3/4, cemiplimab 1/1, and camrelizumab 1/1) used three or more methods of internal evaluation ( 21 – 23 , 28 , 32 – 36 ).…”