Expression of programmed cell death ligand-1 (PD-L1) protein is an adaptive immune response that helps tumours evade detection and elimination by the immune system. PD-L1 can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumour cells and tumour-associated immune cells in tumour microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation and cytokine production.
Durvalumab is a fully human, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that selectively blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Durvalumab does not induce antibody dependent cell-mediated cytotoxicity (ADCC). Selective blockade of PD-L1/PD-1 and PD-L1/CD80 interactions enhances antitumour immune responses and increases T-cell activation.
The combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor functions to enhance anti-tumour T-cell activation and function at multiple stages of the immune response resulting in improved anti-tumour responses. In murine syngeneic tumour models, dual blockade of PD-L1 and CTLA-4 resulted in enhanced anti-tumour activity.
The pharmacokinetics (PK) of durvalumab was assessed for durvalumab as a single agent, in combination with chemotherapy, in combination with tremelimumab and platinum-based chemotherapy, in combination with tremelimumab and in combination with platinum-based chemotherapy followed by durvalumab in combination with olaparib.
The PK of durvalumab was studied in 2903 patients with solid tumours with doses ranging from 0.1 to 20 mg/kg administered intravenously once every two, three or four weeks as monotherapy. PK exposure increased more than dose-proportionally (non-linear PK) at doses <3 mg/kg, and dose proportionally (linear PK) at doses ≥3 mg/kg. Steady state was achieved at approximately 16 weeks. Based on population PK analysis that included 1878 patients who received durvalumab monotherapy in the dose range of ≥10 mg/kg every 2 weeks, the geometric mean steady state volume of distribution (Vss) was 5.64 L. Durvalumab clearance (CL) decreased over time resulting in a geometric mean steady state clearance (CLss) of 8.16 ml/h at Day 365; the decrease in CLss was not considered clinically relevant. The terminal half-life (t1/2), based on baseline CL, was approximately 18 days. There was no clinically meaningful difference between the PK of durvalumab as a single agent, in combination with chemotherapy, in combination with tremelimumab and platinum-based chemotherapy, in combination with tremelimumab and in combination with platinum-based chemotherapy followed by durvalumab in combination with olaparib. The primary elimination pathways of durvalumab are protein catabolism via reticuloendothelial system or target mediated disposition.
Age (19-96 years), body weight (31-149 kg), gender, positive anti-drug antibody (ADA) status, albumin levels, LDH levels, creatinine levels, soluble PD-L1, tumour type, race or ECOG status had no clinically significant effect on the PK of durvalumab.
Mild (creatinine clearance (CrCL) 60 to 89 ml/min) and moderate renal impairment (creatinine clearance (CrCL) 30 to 59 ml/min) had no clinically significant effect on the PK of durvalumab. The effect of severe renal impairment (CrCL 15 to 29 ml/min) on the PK of durvalumab is unknown; however, as IgG monoclonal antibodies are not primarily cleared via renal pathways, a change in renal function is not expected to influence durvalumab exposure.
Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1.0 to 1.5 x ULN and any AST) or moderate hepatic impairment (bilirubin >1.5 to 3 x ULN and any AST) had no clinically significant effect on the PK of durvalumab. The effect of severe hepatic impairment (bilirubin >3.0 x ULN and any AST) on the pharmacokinetics of durvalumab is unknown; however, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence durvalumab exposure.
The PK of durvalumab in combination with tremelimumab was evaluated in a study of 50 paediatric patients with an age range from 1 to 17 years in study D419EC00001. Patients received either durvalumab 20 mg/kg in combination with tremelimumab 1 mg/kg or durvalumab 30 mg/kg in combination with tremelimumab 1 mg/kg intravenously every 4 weeks for 4 cycles, followed by durvalumab as monotherapy every 4 weeks. Based on population PK analysis, durvalumab systemic exposure in paediatric patients ≥35 kg receiving durvalumab 20 mg/kg every 4 weeks was similar to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks, whereas in paediatric patients (≥35 kg) receiving durvalumab 30mg/kg every 4 weeks, exposure was approximately 1.5 fold higher compared to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks. In paediatric patients <35 kg receiving durvalumab 30 mg/kg every 4 weeks, the systemic exposure was similar to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks.
The carcinogenic and genotoxic potential of durvalumab has not been evaluated.
As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the foetus, and in mouse allogeneic pregnancy models disruption of PD-L1 signalling was shown to result in an increase in foetal loss. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery, at exposure levels approximately 18-times higher than those observed at the clinical dose of 10 mg/kg of durvalumab (based on AUC), was associated with placental transfer but not with maternal toxicity or effects on embryofoetal development, pregnancy outcome or postnatal development. Negligible levels of durvalumab was found in milk of cynomolgous monkey on Day 28 after birth.
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