Population pharmacokinetics and exposure-response relationships of dostarlimab in primary advanced or recurrent endometrial cancer in part 1 of RUBY

Abstract

Aims: Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure-efficacy/safety (ER) relationships.

Methods: A PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure-safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure-efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression-free survival (PFS).

Results: For the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure-safety or exposure-PFS relationships.

Conclusions: The addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure-safety or exposure-PFS relationships.

Keywords: clinical pharmacology; oncology; pharmacokinetics; therapeutics.

FIGURE 1

Prediction‐corrected visual predicative check by therapy. Solid blue line: median of the observed dostarlimab concentrations. Dashed lines: 2.5th and 97.5th percentiles of the observed dostarlimab concentrations. Shaded areas: 95% confidence intervals around the prediction‐corrected median (green area) and 2.5th and 97.5th percentiles of the simulated concentrations (grey areas). Grey circles: observations. Orange lines: binning intervals for the visual predictive check. All observations and predictions are adjusted using prediction correction as described in Bergstrand et al. Visual predictive checks are based on data from RUBY Part 1. To increase visibility, the x‐axis was cut at 10 weeks.

FIGURE 2

Forest plots illustrating the covariate effects on exposure at steady state (dostarlimab 1000 mg Q6W). Forest plots of AUC_ss, C _max,ss and C _min,ss ratios as compared to median reference patient (female, 70 kg, age, 64 years, albumin, 39 g/L and ALT, 17 U/L). The distributions represent the ratios based on 1000 sets of parameter estimates resampled from the variance covariance matrix. Plotted numbers: actual percentage of each distribution in a bounded region (here, the central reference line). Grey area: represents the 0.8 and 1.25 boundaries. ALT, alanine aminotransferase; AUC_ss, area under the concentration–time curve at steady state; C _max,ss, maximum concentration at steady state; C _min,ss, minimum concentration at steady state.

FIGURE 3

PFS vs. time, stratified by (A) AUC, (B) C _max, and (C) C _min exposure quartiles. AUC and C _max during the first 21 days; C _min at day 21. Lines: PFS probability. Vertical lines: censoring. Shaded areas: 95% confidence intervals. Parentheses: excluded endpoints. Brackets: included endpoints. AUC, area under the curve; C _max, maximum concentration; C _min, minimum concentration; PFS, progression‐free survival; Q, quartile.

FIGURE 4

PFS vs. time, stratified by tumour MMR/MSI status. Lines: PFS probability. Vertical lines: censoring. Shaded areas: 95% CI. dMMR, mismatch repair deficient; MMR, mismatch repair; MMRp, mismatch repair proficient; MSI, microsatellite instability; MSI‐H, microsatellite instability–high; MSS, microsatellite stable; PFS, progression‐free survival.

FIGURE 5

Rash vs. exposure metrics: all cycles. AUC and C _max during the first 21 days; C _min at day 21. Lines: predicted probability. Shaded areas: 95% confidence intervals. Circles: data. AUC, area under the curve; C _max, maximum concentration; C _min, minimum concentration; CP, carboplatin‐paclitaxel.

FIGURE 6

Arthralgia vs. exposure metrics: cycle 7 and beyond. AUC and C _max during the first 21 days; C _min at day 21. Lines: indicate predicted probability. Shaded areas: 95% confidence intervals. Circles: data. AUC, area under the curve; C _max, maximum concentration; C _min, minimum concentration; CP, carboplatin‐paclitaxel.