Exposure-Response Analysis Highlights Optimal Dosing for Lurbinectedin in SCLC

Lurbinectedin (Zepzelca) given at dose of 3.2 mg/m2 every 3 weeks was found to have a favorable risk/benefit profile in a population of patients with small cell lung cancer (SCLC), according to results from the exposure-response analysis conducted during the phase 2 B-005 trial (NCT02454972).

Patients were given between 0.02 mg/m2 and 6.9 mg/m2 at 2 possible dose regimens of either day 1 or days 1 and 8 of each 3-week cycle for the benefit-risk ratio of the analysis. The dose of 3.2 mg/m2 was determined to be the optimal dose by which to achieve a median area under the unbound plasma concentration-time curve (AUCu) of 1400 ng.h/L, the midpoint of the range of values by which lurbinectedin treatment resulted in the greatest risk/benefit ratio.

“This integrated exposure-response analysis indicates that lurbinectedin exposure was significantly associated with efficacy and safety outcomes. Maximal [overall response rate; ORR] and [overall survival; OS] were found in patients with AUCu from approximately 1400 ng.h/L and 1000 ng.h/L, respectively, which may reveal that ORR is a more treatment directly linked outcome and, therefore, more AUCu dependent, while OS may be more affected by other factors after treatment with lurbinectedin,” investigators of the study wrote.

In the study, 99 patients were administered single-agent lurbinectedin for the efficacy analysis; additionally, 644 patients with solid tumors who received the monotherapy comprised the exposure-safety analysis. A total of 9176 plasma concentrations were used from 755 patients who were given a range of lurbinectedin doses.

The investigators determined the time course of total plasma concentration of lurbinectedin to have an initial half-life of 8 to 9 minutes, followed by slower subsequent half-life of 1.9 hours, and a terminal half-life of 51 hours. The second phase was the majority portion of the overall AUC. The median range of lurbinectedin total plasma area under the concentration– time curve (AUCtot) was 493 μg.h/L (range, 176-1083) and AUCu was 1400 ng.h/L (range, 433-3136) at the 3.2 mg/m2 dose. 

Maximum ORR was 69.1% (95% CI, 49.3%-83.8%) and 18.1% (95% CI, 7.7%-37.1%) for patients with chemotherapy-sensitive and -resistant SCLC, respectively, which was reached at a 95% confidence interval for corresponding AUCu above 1337 and 1433 mg.h/L.

Those with resistant SCLC had median OS times of 3.81 months (95% CI, 0.92-4.37) and 6.24 months (95% CI, 4.27-8.08) in the first and second through fourth quartiles, respectively, while those with sensitive SCLC had corresponding times of 7.26 months (95% CI, 3.22-7.79) and 15.90 months (95% CI, 10.87-19.29). A Cox regression analysis that included both chemotherapy sensitivity and AUCu as continuous variables, with hazard ratios of 0.22 (95% CI, 0.12-0.39) and 0.41 (95% CI, 0.23-0.72), respectively. Analyses of both variables translate to patients with resistant vs sensitive disease having a 4.6-fold higher-risk in death, and a 2.5-fold lower risk of death per unit increase in AUCu.

At the recommended dose and at 20% dose reductions of 2.6 mg/m2 and 2.0 mg/m2, incidence of grade 4 neutropenia is expected to be lowered to 11.3% (95% CI, 11.2%-11.4%) at 2.6 mg/m2 and 7.5% (95% CI, 7.4-7.7) at 2.0 mg/m2 vs 16.5% (95% CI, 16.4%-16.6%) observed at 3.2 mg/m2.

“One or two sequential 20% dose reductions during the course of lurbinectedin treatment are adequate to manage patients who develop severe episodes of myelosuppression,” the investigators concluded.

Reference

Fernández-Teruel C, Fudio S, Lubomirov R. Integrated exposure-response analysis of efficacy and safety of lurbinectedin to support the dose regimen in small-cell lung cancer. Cancer Chemother Pharmacol. Published online November 5, 2021. doi:10.1007/s00280-021-04366-3