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.

Purpose: This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia’s corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration–∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors.Methods: Patients with QTcF ≤ 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m²as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was < 20 ms. C-∆QTcF was explored using linear mixed-effects analysis.Results: A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at C_maxwas 7.81 ms, also below the 10 ms threshold of clinical concern.Conclusions: ECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.

Introduction: Lurbinectedin is a selective inhibitor of oncogenic transcription U.S. Food and Drug Administration (FDA)-approved for patients with relapsed small cell lung cancer (SCLC) as monotherapy at 3.2 mg/m² every 3 weeks (q3wk). ATLANTIS was a phase 3 study in SCLC with lurbinectedin 2.0 mg/m² plus doxorubicin 40 mg/m² q3wk vs physician’s choice, with overall survival (OS) as the primary endpoint and objective response rate (ORR) as the secondary endpoint. This work aimed to dissect the contribution of lurbinectedin and doxorubicin to antitumor effects in SCLC, and to predict the efficacy of single-agent lurbinectedin at 3.2 mg/m² in ATLANTIS to allow for a head-to-head comparison with the control arm.Methods: The dataset included exposure and efficacy data from 387 patients with relapsed SCLC (ATLANTIS, n=288; study B-005, n=99). Patients in the ATLANTIS control arm (n=289) were used for comparison. Unbound plasma lurbinectedin area under the concentration-time curve (AUC_u) and total plasma doxorubicin area under the concentration-time curve (AUC_DOX) were used as exposure metrics. Univariate and multivariate analyses were conducted to determine the best predictors and predictive model for OS and ORR. OS baseline hazard was best described by a log-logistic distribution, with chemotherapy-free interval (CTFI), lactate dehydrogenase, albumin, brain metastases, neutrophils/lymphocytes ratio, AUC_u, and the interaction between AUC_u and AUC_DOX as predictors. Effect of AUC_u on ORR best fitted to a sigmoid-maximal response (E_max) logistic model, where E_max was dependent on CTFI.Results: Head-to-head comparisons with predicted 3.2 mg/m² lurbinectedin resulted in a positive outcome in ATLANTIS, with hazard ratio (95% prediction intervals [95% PI]) for OS of 0.54 (0.41, 0.72), and odds ratio (95% PI) for ORR of 0.35 (0.25, 0.5).Conclusion: These results support the superiority of lurbinectedin monotherapy for relapsed SCLC over other approved therapies.

This open-label, two-part, phase Ib drug–drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m², 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m², 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m² + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for C_max, area under the curve (AUC) 2.4-fold for AUC_0–t and 2.7-fold for AUC_0–∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.