Abstract P1-04-03: Model-predicted Neurokinin-1 (NK1) Receptor Occupancy of Netupitant versus Aprepitant Over an Extended Time Period: Implications for Controlling Nausea and Vomiting Associated with Antibody-Drug Conjugates (ADCs)

Abstract Background: Nausea and vomiting (NV) are expected side effects of anticancer treatment and have traditionally been assessed up to 120 h (5 days) post-treatment. However, following a recent systematic review by Chow et al. (Supp Care Cancer 2023) which assessed the prevalence of “long-delayed” NV (beyond 120 h), attention has begun shift to this unmet need, particularly as data emerges with novel targeted therapies such as ADCs. Evolving data with ADCs in breast cancer indicates NV are not only among the most frequent treatment-related side effects but can occur for a longer time, potentially resulting in detrimental effects on quality of life and on maintaining dose-intensity. Using guideline-recommended antiemetic prophylaxis [i.e., an NK1 receptor antagonist (RA)-containing regimen] when initiating ADCs is critical to optimize patient outcomes. Netupitant (NETU), a highly selective NK1 RA used in combination with palonosetron, has shown favorable comparative efficacy to an aprepitant (APR) regimen up to 168 h, likely due in part to its longer half-life. As receptor occupancy (RO) is assumed to serve as proxy for clinical efficacy, we conducted an analysis aimed at evaluating the RO in the brain striatum with netupitant versus aprepitant for an extended time interval. Methods: Mean plasma concentration-time curves of NETU and APR from previous pharmacokinetic (PK) studies in the Caucasian population were analyzed by compartmental PK modelling upon single administration of the therapeutic doses of 300 mg and 125 mg po, respectively. Emax pharmacodynamic (PD) models were fitted to the % NK1 RO data in the striatum region after NETU and APR administrations as a function of PK model predicted plasma concentrations. The % NK1 RO in the striatum region up to 480 h for 300 mg NETU on day 1 versus 3-day APR (125 mg day 1 and 80 mg days 2-3) were then assessed by PK/PD model predictions. Results: The RO patterns for NETU and APR were quite distinct. The NK1 RO reached 90% by 3 h for both agents. RO remained high up to 120 h (day 5) for both NETU (76%) and APR (81%) but then dropped substantially for APR and gradually declined for NETU. At 168 h (day 7), the RO was 70% for NETU and 39% for APR. The RO for NETU and APR, respectively, at 192 h (day 8), 240 h (day 10), and 480 h (day 20) was 67% vs 19%, 60% vs 3%, and 22% vs 0%. Conclusions: There was a persistent and gradual decline of % NK1 RO over a period of 20 days following a single dose of NETU compared with a rapid decline in RO for APR after 6 days. These findings suggest that NETU has the potential to prevent NV over a prolonged duration, making it a promising antiemetic for prevention of NV with new anticancer targeted therapy like some ADCs. Preserving patients’ quality of life and ensuring uninterrupted treatment is vital to optimizing outcomes and maximizing treatment effectiveness. Citation Format: Matti Aapro, Hirotoshi Iihara, Silvia Olivari Tilola, Alberto Bernareggi. Model-predicted Neurokinin-1 (NK1) Receptor Occupancy of Netupitant versus Aprepitant Over an Extended Time Period: Implications for Controlling Nausea and Vomiting Associated with Antibody-Drug Conjugates (ADCs) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-04-03.