Lei Sun (1), Tomomi Matsuura (2), Cesar Pichardo-Almarza (2^), Rita Dalal (1), Bhaskar Rege (1)*
(1) Alkermes, Inc., Waltham, MA, USA, (2) Certara UK Ltd, Simcyp Division, Canterbury, UK, (2^) Certara UK Ltd, Simcyp Division, Canterbury, UK (at time of study). *Corresponding author: Bhaskar.Rege@alkermes.com
Objectives:
Nemvaleukin is a novel engineered protein designed to selectively bind the intermediate-affinity interleukin-2 receptor, preferentially expanding antitumor CD8+ T and natural killer (NK) cells, with minimal effect on immunosuppressive regulatory T cells (Tregs). In ARTISTRY-1 (NCT02799095), intravenous (IV) nemvaleukin once daily on days 1-5 (QDx5) in a 21-day cycle showed antitumor activity across multiple tumor types as monotherapy at the recommended phase 2 dose of 6 μg/kg/d, and in combination with pembrolizumab at 3 μg/kg/d and 6 μg/kg/d. Antitumor activity correlated with expansion of circulating CD8+ T and NK cells, with minimal effect on Tregs. We hypothesize that alternative doses and dosing schedules may retain efficacy while reducing the need for QDx5 dosing, which can be difficult for some patients and medical staff. Quantitative System Pharmacology (QSP) modeling was applied to predict less frequent IV dosing regimens that would result in expansion of CD8+ T and NK cells similar to that achieved with 3 μg/kg/d QDx5 and 6 μg/kg/d QDx5.
Methods:
A QSP model for nemvaleukin was developed using MATLAB and SimBiology by leveraging published literature data and calibrated with in vitro pSTAT5 data and in vivo clinical data. The model was verified by comparing simulated cell counts in peripheral blood with observed clinical data and applied to predict the change in CD8+ T and NK cells in peripheral blood and in tumor in response to IV nemvaleukin given as 1 dose, 2 doses, or 3 doses in a 21-day cycle.
Results:
The QSP model-predicted time course of circulating CD8+ T and NK cells described ARTISTRY-1 clinical data reasonably well. Application of this model predicted that, as part of a 21-day cycle, a) a single nemvaleukin dose of ≥30 μg/kg, b) 2 doses of ≥20 μg/kg/dose with a longer interval, c) 2 doses of 15 μg/kg/dose with a shorter interval, d) 3 doses of 20 μg/kg/dose with a longer interval, and e) 3 doses of 15 μg/kg/dose with a shorter interval would result in CD8+ T and NK cell expansion comparable to that achieved with nemvaleukin 6 μg/kg/d QDx5. The model also predicted that lower dose levels given on the aforementioned schedules are required to achieve CD8+ T and NK cell expansion comparable to that achieved with 3 μg/kg/d QDx5. Based on these findings and additional data, a protocol amendment was made to the ongoing phase 1/2 ARTISTRY-3 trial (NCT04592653) to add a new cohort (Cohort 2) that will assess the safety and tolerability of escalating doses of nemvaleukin given at 1 or 2 doses per 21-day cycle in patients with advanced solid tumors.
Conclusions:
Nemvaleukin QDx5 has demonstrated antitumor activity across multiple tumor types as monotherapy and in combination. An optimal dosing schedule would be the fewest doses in a treatment cycle to increase recovery time between doses and simplify administration when given in combination with current standard-of-care treatments, thus providing flexibility for patients, caregivers, and clinics. QSP modeling predicted doses and less frequent dosing schedules that retain antitumor activity and the unique cell expansion profile of nemvaleukin, and also predicted that target immune cell expansion observed with nemvaleukin at 3 µg/kg/d QDx5 and 6 µg/kg/d QDx5 may be achieved with a higher single dose in a 21-day cycle. Additionally, 2 doses in a 21-day cycle may achieve target cell expansion at a lower dose compared with the single-dose schedule. Accordingly, a new cohort was added in the ongoing ARTISTRY-3 trial to evaluate the effects of 1 or 2 doses of nemvaleukin per 21-day cycle when administered as monotherapy or in combination with pembrolizumab.
Reference: PAGE 30 (2022) Abstr 10213 [www.page-meeting.org/?abstract=10213]
Poster: Drug/Disease Modelling - Oncology