Purpose: Durvalumab (Imfinzi™) is a human mAb that binds to PD-L1 and blocks its interaction with PD-1 and CD80. Olaparib (Lynparza™) is a poly (ADP-ribose) polymerase inhibitor (PARPi). PARP inhibition may upregulate PD-L1 expression, and increased DNA-damage induced by olaparib may enhance immune recognition. The objectives of this analysis were to develop a population pharmacokinetic (PPK) model of durvalumab after combination therapy with olaparib, to assess the association between patient demographics and disease characteristics on durvalumab PK, and to quantify durvalumab exposure -response (ER) and its relationship with efficacy and safety.
Methods: A total of 137 patients with advanced solid tumors (SCLC, breast, ovarian and gastric cancer) from a phase I/II study (MEDIOLA) were included in PPK modeling of durvalumab. Various covariates were evaluated, including patient characteristics (age, sex, body weight), baseline tumor size and biomarkers (albumin, bilirubin, creatinine, neutrophil to lymphocyte ratio (NLR), using a full covariate model approach. PPK model was used to predict the baseline and steady-state clearance based on the empirical post hoc estimate. Exposure – response analysis for safety was conducted using logistic regression.
Results: A two-compartment model with time variant clearance (CL) adequately described durvalumab PK data. Sex and body weight were identified as significant covariates on CL; females had approximately 23% lower clearance of durvalumab than males and clearance slightly increased with increasing body weight; although these covariates were statistically significant but were not considered clinically relevant since the mean change in CL was <30%. Durvalumab CL decreases over time with a mean maximum reduction of ~20%. Analysis showed that CL values were associated with disease status suggesting association with a decrease in non-specific protein catabolic rate among cancer patients who benefit from therapy: CL at steady-state (CLss) for patients with complete response (CR) were approximately 40% lower than patients with progressive disease (PD). Overall, no association was observed between durvalumab PK exposure levels (Cmax,1, Ctrough,2, and Ctrough,ss) and durvalumab related AE incidence based on patients that received durvalumab 1500 mg IV q4w plus olaparib 300 mg po bid. For Grade 3+ AE, higher durvalumab PK exposure was not associated with an increased risk of AE.
Conclusion: A time-variant clearance was identified for durvalumab and CL decreased when disease status improved following combination therapy of durvalumab plus olaparib. ER analysis for safety demonstrated a flat relationship between drug related grade 3+ AE and durvalumab exposure.