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DURVALUMAB
Durvalumab (Imfinzi™, MEDI 4736) is a fully human immunoglobulin G1k monoclonal antibody against PD-L1, which is being developed by Astra Zeneca for cancer treatment (Figures 1 and 2).13,14PD-L1 binds to programmed cell death-1 (PD-1) and CD80 (B7-1) receptors, resulting in inhibition of T-cell function. A broad range of human tumors upregulate PD-L1, evading immune surveillance and antitumor T-cell responses. Durvalumab binds to PD-L1 with high affinity and specificity, blocking its interactions with PD-1 and CD80, resulting in enhanced activation of T-cells against tumor cells (TCs). It does not bind to PD-L2.
Durvalumab is given every 2 weeks intravenously at 10 mg/kg over 60 minutes. Pharmacodynamics parameters showed a concentration-dependent inhibition of PD-L1 in an anti-CD3-based T-cell activation assay and a mixed lymphocyte reaction assay.14 Exposure to durvalumab increases dose-proportionally at C3 mg/kg in cancer patients, with steady-state levels observed at around 16 weeks.15 Durvalumab clearance decreases over time but is not considered clinically relevant; the geometric mean terminal half-life of durvalumab is around 17 days.15 The pharmacokinetics of durvalumab are not affected by age (19–96 years), body-weight (34–149 kg), sex, race, tumor type, PS, levels of albumin, lactate dehydrogenase, creatinine or soluble PD-L1, mild or moderate renal impairment (creatinine clearance 60–89 and 30–59 mL/minute, respectively) or mild hepatic impairment (bilirubin ≤ upper limit of normal [ULN] and AST > ULN or bilirubin >1.0–1.5 times ULN and any AST). No data are available in severe renal or hepatic impairment.
Efficacy and Safety in UC
Durvalumab was evaluated in a Phase I/II study in all solid tumors (Table 2).16 Subjects received durvalumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicities, or a maximum duration of 12 months. After the treatment course, patients were offered a retreatment course of another 12 months. The initial 20 patients were enrolled regardless of PDL-1 expression. PD-L1 was defined as positive if either ≥25% of TC or ≥25% of immune cells (IC) expressed PD-L1. In UC patients, most of them (93.4%) had received ≥1 prior lines of platinum-based chemotherapy, 29.5% had liver metastases.16
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