Population Pharmacokinetics and Exposure-response Analysis of Durvalumab in Patients with Limited-stage Small-cell Lung Cancer in the Phase 3 ADRIATIC Study.

Durvalumab monotherapy as a consolidation treatment for limited-stage small-cell lung cancer (LS-SCLC) demonstrated a favourable benefit-risk profile in the ADRIATIC study. We evaluated population pharmacokinetics (PopPK) and exposure-response (E-R) relationships of durvalumab in patients with LS-SCLC. The durvalumab PopPK model was updated by integrating PK data from the ADRIATIC study. Individual exposure metrics were derived from empirical Bayes estimates for E-R analyses relating to safety (adverse events [AEs]) and efficacy (progression-free survival [PFS] and overall survival [OS]). A two-compartment model with a time-dependent clearance adequately characterized durvalumab PK data. The typical parameter estimates for baseline clearance, central and peripheral volume of distribution were 0.273 L/day, 3.49 L and 2.35 L, respectively. All identified covariates are considered to have minimal clinical impact on durvalumab PK parameters with effect within 80-125% of typical values. Kaplan Meier plots of PFS or OS stratified by exposure quartiles suggested a plateaued relationship between durvalumab exposure and PFS or OS at the selected dose level of 1500 mg. The Cox PH model analysis did not identify exposure metrics as significant prognostic factors for the OS or PFS hazard. At 1500 mg IV Q4W, a flat E-R relationship was observed between durvalumab PK exposure and safety endpoints including Grade 3 + treatment-related AEs, Grade 3 + treatment-related AEs of special interest, and AEs leading to treatment discontinuation. The results support the use of durvalumab monotherapy for the patients with LS-SCLC, and no dose adjustment is considered necessary based on the PopPK and E-R analyses. NCT03703297.