Recommended phase 2 dose (RP2D) of nemvaleukin alfa in patients (pts) with advanced solid tumors treated with less frequent intravenous (IV) dosing (ARTISTRY-3).
Authors: Piha-Paul Sarina A. , Call Justin A , Spira Alexander I. , Bartolome Jorge , de Miguel Maria J. , Du Yangchun , DiLea Clifford , Panchabhai Sonali , Lakhani Nehal J. 
Published: June 2024

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Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokinedesigned to preferentially expand CD8+ T and natural killer (NK) cells with minimal effect on regulatory T cells (Tregs). In ARTISTRY-1, IV nemvaleukin at 6 μg/kg once daily, days 1-5 (QD×5) in a 21-day (D) cycle showed antitumor activity across multiple tumors alone and in combination with pembrolizumab (1). ARTISTRY-3 (NCT04592653) is a phase 1/2, open-label study evaluating less frequent IV nemvaleukin dosing in advanced solid tumors. We report pharmacodynamic (PD) and pharmacokinetic (PK) results from ARTISTRY-3. Methods: Pts with select solid tumors having exhausted the standard of care therapies were eligible. Quantitative systems pharmacology modeling using different doses of nemvaleukin and schedules was employed to predict less frequent IV dosing that could achieve CD8+ and NK cell expansion comparable to that of 6 µg/kg or 3 µg/kg QD×5 in a 21-D cycle. Based on this information, using Bayesian optimal interval design, escalating doses of nemvaleukin (10-40 μg/kg/d) were evaluated across 3 dosing schedules in a 21-D cycle: D1, D1+D8, and D1+D4. Primary endpoint was incidence of dose-limiting toxicities (DLTs) from the first dose through the end of DLT observation period. Secondary endpoints included objective response, PK, and safety. PD assessments included baseline and on-treatment absolute cell counts (CD8+ T, CD4+ T, NK, CD19+ B, Treg) and relative percentages of memory and activated T cells and NK cell subtypes. Results: As of Jan 1, 2024, 49 pts have been treated: 17, 13, and 19 in schedules 1, 2, and 3, respectively. No DLTs have been reported. NK and CD8+ T cell expansion was seen at all doses in all schedules, thus confirming the PD effect of nemvaleukin. Dose-response relationship was observed for PD markers across all schedules. Fold change from baseline for absolute count of NK and CD8+ T cells was significantly higher in schedules 2 and 3, along with better stabilization of disease (SD> 12-24 weeks). Minimal to no expansion of Tregs was observed across all schedules. Safety profile was consistent with nemvaleukin mechanism of action and as expected in pts with relapsed/refractory solid tumors. Most treatment-related adverse events (TRAEs) were grade (G) 1-2. There were 3 G3 TRAEs: anemia (schedule 2, 20 µg/kg) and neutropenia and decreased white blood cell count (both schedule 3). There were no G ≥4 TRAEs. Nemvaleukin exposure (Cmax and AUCinf) increased with escalating doses, with no evidence of nonlinearity. Conclusions: Nemvaleukin demonstrated PD proof of mechanism in all 3 schedules and was tolerable at all doses tested, with some stabilization of disease. Safety profile was similar across all schedules. Nemvaleukin RP2D for less frequent dosing schedule is expected to be completed in Q1 2024. 1. Vaishampayan U et al. J Clin Oncol 2022. Abs #2500. Clinical trial information: NCT04592653 .