1793P RESILIENT part 1: Pharmacokinetics of second-line (2L) liposomal irinotecan in patients with small cell lung cancer (SCLC)

Abstract

RESILIENT (NCT03088813) is a two-part phase 2/3 study of the safety, tolerability and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy. Here we describe the pharmacokinetics (PK) of 2L liposomal irinotecan from RESILIENT part 1. Part 1 was an open-label, single-arm study comprising dose-finding and dose-expansion phases. Patients aged ≥ 18 years, with an ECOG performance status of 0/1, received liposomal irinotecan 70 or 85 mg/m2 free base every 2 weeks. Seven PK samples per patient were scheduled. Plasma concentration data for total irinotecan (tIRI) and SN-38 (active metabolite) were analysed using a population PK model updated for SCLC. PK parameters were estimated with non-linear mixed effects modelling. Assessment of model adequacy was based on the uncertainty of parameter estimates and advanced evaluation methods (e.g. visual predictive check). Interindividual variability was examined using potential covariates including patient demographics and UGT1A1*28 genotype status. Derived PK parameters, Caverage and Cmax, were computed by dose from individually predicted PK profiles. As of 2 DEC 2019, 30 patients had received liposomal irinotecan (70 mg/m2, n = 25; 85 mg/m2, n = 5). tIRI PK is described by a two-compartment model with first-order elimination. SN-38 is formed directly by a first-order constant from the central compartment of liposomal irinotecan or following a transit compartment. UGT1A1*28 *7/*7 homozygous status (4/30 patients) was not associated with a significant impact on SN-38 clearance. Model evaluation was satisfactory for both tIRI and SN-38. After 70 and 85 mg/m2 respectively, median (coefficient of variation %) Caverage was 5.1 (48) and 5.5 (9) μg/mL for tIRI, and 1.6 (33) and 2.1 (16) ng/mL for SN-38, and Cmax was 36.1 (15) and 40.7 (14) μg/mL for tIRI and 3.7 (32) and 4.4 (10) ng/mL for SN-38. The PK of 2L liposomal irinotecan and SN-38 in patients with SCLC is well described by the population model. Findings suggest SN-38 clearance is not associated with UGT1A1*28 *7/*7 homozygous status. RESILIENT part 2 data will be added to the current dataset to enrich the PK characterization.