Integrated exposure–response analysis of efficacy and safety of lurbinectedin to support the dose regimen in small-cell lung cancer

Purpose These exposure–response (E–R) analyses integrated lurbinectedin effects on key efficacy and safety variables in relapsed SCLC to determine the adequacy of the dose regimen of 3.2 mg/m 2 1-h intravenous infusion every 3 weeks (q3wk). Methods Logistic models and Cox regression analyses were applied to correlate lurbinectedin exposure metrics (AUC tot and AUC u ) with efficacy and safety endpoints: objective response rate (ORR) and overall survival (OS) in SCLC patients ( n = 99) treated in study B-005 with 3.2 mg/m 2 q3wk, and incidence of grade 4 (G4) neutropenia and grade 3–4 (G ≥ 3) thrombocytopenia in a pool of cancer patients from single-agent phase I to III studies ( n = 692) treated at a wide range of doses. A clinical utility index was used to assess the appropriateness of the selected dose. Results Effect of lurbinectedin AUC u on ORR best fitted to a sigmoid-maximal response ( E max ) logistic model, where E max was dependent on chemotherapy-free interval (CTFI). Cox regression analysis with OS found relationships with both CTFI and AUC u . An E max logistic model for G4 neutropenia and a linear logistic model for G ≥ 3 thrombocytopenia, which retained platelets and albumin at baseline and body surface area, best fitted to AUC tot and AUC u . AUC u between approximately 1000 and 1700 ng·h/L provided the best benefit/risk ratio, and the dose of 3.2 mg/m 2 provided median AUC u of 1400 ng·h/L, thus maximizing the proportion of patients within that lurbinectedin target exposure range. Conclusions The relationships evidenced in this integrated E–R analysis support a favorable benefit-risk profile for lurbinectedin 3.2 mg/m 2 q3wk. Trial registration Clinicaltrials.gov: NCT02454972; registered May 27, 2015.