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 (AUCtot and AUCu) 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 AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on chemotherapy-free interval (CTFI). Cox regression analysis with OS found relationships with both CTFI and AUCu. An Emax 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 AUCtot and AUCu. AUCu between approximately 1000 and 1700 ng·h/L provided the best benefit/risk ratio, and the dose of 3.2 mg/m2 provided median AUCu 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.

Conflict of interest statement

Salvador Fudio and Rubin Lubomirov are employees of Pharma Mar. Carlos Fernández-Teruel is a former employee of Pharma Mar. All authors may hold Pharma Mar stock or stock options.

© 2021. The Author(s).

Figures

Fig. 1

Relationship between ORR by IRC and AUCu stratified by CTFI. Solid black dots represent the proportion of responders grouped by quartiles of AUCu and plotted at the median AUCu for each quartile in resistant (a) and sensitive (b) patients. Bars represent the 95% CI for the proportion of each quartile. Curve and blue shaded area represent predicted values and 95% CI of model-predicted ORR, respectively. The vertical point lines and the gray shaded area represent the 95% prediction interval of the observed AUCu. AUCu unbound plasma area under the concentration–time curve, CI confidence interval, CTFI chemotherapy-free interval, IRC independent review committee, ORR objective response rate

Fig. 2

Kaplan–Meier plots for OS versus pooled AUCu (first vs. second to fourth quartiles), stratified by CTFI (a, resistant; b, sensitive). Q1 AUCu: first quartile of AUCu; Q2–4 AUCu: second to fourth quartiles of AUCu. AUCu unbound plasma area under the concentration–time curve, CTFI chemotherapy-free interval, OS overall survival

Fig. 3

Relationship between AUCu and G4 neutropenia (a) and G ≥ 3 thrombocytopenia (b). Solid black dots represent the G4 neutropenia or G ≥ 3 thrombocytopenia incidence grouped by quartiles of AUCu and plotted at the median AUCu for each quartile. The bars represent the 95% confidence interval for the proportion of each quartile. Curve and blue shaded area represent predicted values and 95% confidence intervals of model-predicted risk of G4 neutropenia or G ≥ 3 thrombocytopenia, respectively. The vertical point lines and the gray shaded area represent the 95% prediction interval of the observed AUCu in patients treated at doses from 0.02 to 6.9 mg/m2. AUCu unbound plasma area under the concentration–time curve, G grade

Fig. 4

Clinical utility index with AUCu in resistant (a) and sensitive (b) SCLC patients. Dashed green vertical line is the lurbinectedin AUCu providing an ORR of 7.5% (resistant) and 19.3% (sensitive), which are the ORRs corresponding to topotecan. Dashed dark red vertical line is the AUCu at which the probability of grade 4 neutropenia is 20%. The gray shaded area represents the 95% prediction interval of the observed AUCu in SCLC patients treated at 3.2 mg/m2. Black dotted vertical lines are percentiles 5, 50, and 95 of AUCu. AUCu unbound plasma area under the concentration–time curve, CUI clinical utility index, G grade, SCLC small-cell lung cancer