Abstract 5060: Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study

Abstract

Abstract Background: Oxaliplatin (OX)-containing regimens are frequently utilized to treat gastrointestinal (GI) cancers. OX is eliminated predominately via urinary excretion (GFR and active tubular secretion). The contribution of active transport via OCT2 and MATE1/2-K to OX clearance is not fully understood. Tyrosine kinase inhibitors (TKIs) are frequently found to interact with OCT2/MATE transporters; however, a gap in knowledge remains between their clinical potential to impact OX pharmacokinetics (PK) and in turn, impact renal function. Tucatinib (TUC) is a highly selective human epidermal growth factor receptor 2 (HER2)-directed TKI approved in multiple regions in combination with trastuzumab and capecitabine for adult patients with metastatic HER2+ breast cancer and is currently being investigated in other HER2+ tumors. TUC inhibits OCT2/MATE-mediated transport of metformin and creatinine in vitro and in vivo. In this study, we investigated the impact of TUC on OX plasma PK, OX renal clearance (Clr), and renal function. Methods: In vitro inhibition of OCT2/MATE-mediated transport of OX by TUC was assessed in OCT2, MATE1, or MATE2-K-expressing MDCK-II cells. SGNTUC-024 (NCT04430738) is a Ph1b/2 clinical study in patients with HER2+ GI cancers evaluating the impact of TUC on the safety and PK of OX. Patients received TUC 150 mg (Cohort 1A) or 300 mg (Cohort 1B) BID starting on C1D8 of a 2-week cycle in combination with modified FOLFOX6/7. Intensive PK was collected in plasma and urine for OX alone (C1D1) or with steady-state TUC (C2D1). Total plasma platinum (Pt, analyzed as a surrogate for OX and catabolites), plasma Pt ultrafiltrate (PUF, unbound), and urine Pt were quantitatively analyzed via ICP-MS. Serum Cystatin C (CysC) was measured as a pharmacodynamic (PD) renal function marker in Cohorts 1A and 1B. Results: TUC inhibited in vitro OX transport by MATE1 (IC50 = 0.0639 µM), MATE2-K (IC50 = 0.0382 µM), and OCT2 (IC50 = 0.491 µM). In 11 patients, total Pt and PUF AUC0-8h geometric mean ratio (GMR) and 90% confidence intervals (CI) between patients who received OX alone compared to in combination were 1.1 (0.98, 1.3) and 1.0 (0.78, 1.4) in Cohort 1A (n=4) and 1.1 (0.96, 1.2) and 1.0 (0.98, 1.1) in Cohort 1B (n=7), respectively. OX GM (%CV) renal clearance (Clr,0-8h in mL/min) and fraction excreted 24h post-dose (fe,0-24h) were similar with and without TUC in both Cohort 1A (C1D1 Clr0-8h = 277 (33), fe,0-24h = 22% (17); C2D1 Clr0-8h = 249 (78), fe,0-24h = 21% (15)) and Cohort 1B (C1D1 Clr0-8h = 189 (37), fe,0-24h = 17.7% (16); C2D1 Clr0-8h = 177 (40), fe,0-24h = 16.6% (35)). Reversible slight increases in CysC (normalized to baseline) on day 3 of each cycle, irrespective of tucatinib, were observed. Conclusions: This investigation of in vitro and in vivo determinants of OX PK demonstrates that TUC does not alter the renal clearance of oxaliplatin nor renal function when OX is administered in combination with TUC. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, Vineet Kumar, Michelle Ubowski, JoAl G. Mayor, Layth I. Abdulrasool, Clark M. Henderson, Joseph A. Ware, Christopher J. Endres. Tucatinib does not alter oxaliplatin PK or associated renal function: An OCT2 and MATE transport inhibition study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5060.