Population pharmacokinetics of selpercatinib in patients with an advanced solid tumor, including RET fusion-positive NSCLC, RET-mutant MTC, and other tumors with increased RET activity
Dan Liu (1), Johan Wallin (1,2), Ayman Akil (3), Craig Comisar (3), Nathan Teuscher (3), Jan-Stefan van der Walt (1)
(1) Global PKPD and Pharmacometrics, Eli Lilly and Company, United Kingdom, (2) Clinical Pharmacology, BioInvent International AB, Sweden, (3) iDD, Certara USA Inc, USA.
Objectives:
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Selpercatinib, a first-in-class highly selective and potent rearranged during transfection (RET) kinase inhibitor with central nervous system activity, is approved in multiple countries for the treatment of RET-altered lung or thyroid cancers. Population PK analyses were performed with data from ongoing Phase 1/2 clinical trials to support the development of selpercatinib in RET fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), and other tumors with increased RET activity [1]. The objectives of the analyses were to identify any intrinsic or extrinsic factor that affects selpercatinib steady-state exposure. |
Methods:
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Data from two ongoing, open-label, multi-centre studies in patients with advanced solid tumors, including RET fusion NSCLC, MTC, and other tumors were analyzed (data cut-off 15 June 2021 for JZJA and data up to 12 April 2021 for JZJK). Study JZJA (LIBRETTO-001) is a Phase 1 (dose escalation)/Phase 2 (dose expansion) study [2]. Study JZJK (LIBRETTO-321) is a Phase 2 study conducted in China [3]. Patients received oral selpercatinib at doses ranging from 20 mg once daily through 240 mg twice daily (BID) during Phase 1. The dose of 160 mg BID was selected for Phase 2. Blood for plasma PK assessment was collected at up to 1 hour predose and at 1, 2, and 4 and 8 hours postdose on Cycle 1 Day 8 (C1D8) with additional plasma PK assessment on C1D1, C3D1, C5D1, and Day 8 of a patient’s new dose (for intrasubject dose escalation). Population PK analyses were performed using nonlinear mixed-effects modeling (NONMEM®; version 7.4.3). |
Results:
A total of 8205 concentration observation records from 844 patients were included. About 90% of the data were from patients dosed with the recommended phase 2 dose (RP2D) of 160 mg BID.
The final model was a 2-compartment disposition model with sequential zero- and first order absorption. Inter-individual variability terms were included on apparent clearance (CL/F), apparent central volume of distribution, first-order absorption rate constant, and duration of zero-order absorption. The residual error model included both additive and proportional error terms.
Selpercatinib CL/F decreased as dose increased from 20 mg once daily through 240 mg BID. This relationship resulted in slightly greater than proportional increases in selpercatinib exposure with increases in doses. Body weight was included following allometric principles. There was a 18% increase in bioavailability for Asian subjects, in addition to effects of dose on CL/F and allometric body weight scaling. However, there was a significant overlap in steady-state AUC and Cmax values in Chinese, Asian, and non-Asian subjects. Moreover, no significant difference was identified between China, Japan, and other Asian subjects. Factors such as sex, age, creatinine clearance, liver function tests, and tumor type had no impact on the population PK of selpercatinib. Simulation showed that the steady-state AUC and Cmax values overlapped considerably for all tumor types (MTC, NSCLC, and tissue-agnostic solid tumors) in patients dosed at the RP2D of 160 mg BID.
Conclusions:
At the RP2D of 160 mg BID, the population PK model that included differences in race (Asian vs non-Asian) and body weight (using allometry) predicted similar steady-state exposure of selpercatinib for Asian and non-Asian patients and across tumor types.
References:
[1] Brandhuber BB, Haas J, Tuch BB, et al. ENA-0490 The development of LOXO-292, a potent, KDR/VEGFR2-sparing RET kinase inhibitor for treating patients with RET-dependent cancers. Poster presented at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2016; Poster No. 441; November 29-December 2, 2016; Munich Germany
[2] ClinicalTrials.gov Identifier: NCT03157128
[3] ClinicalTrials.gov Identifier: NCT04280081