Population pharmacokinetics and exposure-response analysis of durvalumab in patients with resectable stage II to IIIB (N2) NSCLC in the phase III AEGEAN study.

[AIMS] In the AEGEAN study, perioperative durvalumab plus platinum-based neoadjuvant chemotherapy for patients with resectable stage II to IIIB (N2) non-small-cell lung cancer (NSCLC) demonstrated a favourable benefit-risk profile. This study evaluated population pharmacokinetics (PopPK) and exposure-response (ER) relationships of durvalumab in patients with resectable NSCLC.

[METHODS] The durvalumab PopPK model was updated by integrating PK data from the AEGEAN study. Individual exposure metrics were derived from empirical Bayes estimates for ER analyses relating to safety (adverse events [AEs]) and efficacy (pathological complete response [pCR] and event-free survival [EFS]).

[RESULTS] A two-compartment model with a time-dependent clearance adequately characterized durvalumab PK data. The typical parameter estimates clearance, central and peripheral volume of distribution were 0.285 L/day (relative standard error: 1.68%), 3.42 L (0.962%) and 2.30 L (2.09%), respectively. All identified covariates caused ≤21% of change on durvalumab PK parameters, indicating no meaningful impact on durvalumab exposure. At the plateaued dose level of durvalumab 1500 mg, a flat relationship was observed between durvalumab PK exposure and EFS, confirmed by Cox proportional hazards analysis, and pCR, confirmed by logistic regression analysis. Logistic regression analysis indicated that no clinically relevant relationships were 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.

[CONCLUSIONS] These results support the novel perioperative durvalumab regimen for patients with resectable NSCLC from the AEGEAN study, and no dose adjustment is necessary based on the PopPK and ER analyses.