ZepZelCa ( Lurbinectedin ) en el 2020 World Conference on Lung Cancer . Poster Presentado el 28 de Enero : La Mejor Dosis Para el Tratamiento de Cancer de Pulmón Microcitico es la de 3,2 Mg/m² .

 Exposure-Response Analyses and Clinical Utility Index to Justify the Dosage of Lurbinectedin in Small-cell Lung Cancer .

Introduction

Lurbinectedin (Zepzelca™) received accelerated approval by the US FDA for the treatment of adults with small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. The analyses presented herein characterized the relationships between lurbinectedin plasma exposure and efficacy or safety, which justify the selected dose regimen of 3.2 mg/m² administered every 3 weeks (q3wk).

Methods

This analysis was based on available exposure and efficacy data from SCLC patients from the phase 2 basket study (n=99) and exposure and safety data from phase 1 to 3 studies of single-agent lurbinectedin administered q3wk (n=644). Total and unbound AUC (AUCtot and AUCu) of lurbinectedin in Cycle 1 were selected as exposure metrics. The primary efficacy endpoint was objective response rate (ORR) by independent review committee. Exposure-ORR was evaluated using multivariate logistic regression models for chemotherapy-free interval: platinum-sensitive (<90 days) versus platinum-resistant (≥90 days). The primary safety endpoint was grade 4 neutropenia, and a multivariate logistic regression model was applied. Clinical utility index (CUI) was defined as the difference between the probability of ORR and the probability of grade 4 neutropenia.

Results

Lurbinectedin unbound exposures between 1000 and 1700 ng·h/L provided the best benefit/risk ratio for lurbinectedin, and the recommended dosing regimen of 3.2 mg/m² q3wk provided a median unbound exposure of 1400 ng·h/L, which maximized the proportion of patients within this lurbinectedin target exposure range. The figure below demonstrates that the dose regimen of 3.2 mg/m² q3wk maximized the probability of ORR without a significant increase in the probability of grade 4 neutropenia. The CUI peaked at this dose regimen in patients with platinum-sensitive or -resistant SCLC.

Conclusion

The recommended lurbinectedin dosing regimen of 3.2 mg/m² q3wk provided maximum benefit in SCLC patients with disease progression on or after platinum-based chemotherapy with manageable probability of grade 4 neutropenia. Lowering the dose resulted in reduced efficacy, whereas increasing the dose led to an increased incidence of severe hematological toxicity without improvement of efficacy.