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

Abstract

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/m² 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/m² 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/m² 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/m² q3wk.

Trial registration: Clinicaltrials.gov: NCT02454972; registered May 27, 2015.

Keywords: Clinical utility index; Exposure–response; Lurbinectedin; Pharmacokinetics; Small-cell lung cancer.