Selection of the recommended phase 2 dose (RP2D) for subcutaneous nemvaleukin alfa: ARTISTRY-2.

Abstract

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Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor to preferentially activate CD8 ⁺ T and natural killer (NK) cells with minimal expansion of regulatory T cells (T _regs), designed for use as a cancer immunotherapy. ARTISTRY-2 (NCT03861793) is an ongoing phase 1/2 study evaluating the safety, efficacy, and pharmacokinetic and pharmacodynamic (PD) responses of subcutaneous (SC) nemvaleukin in combination with pembrolizumab in patients (pts) with advanced solid tumors. Methods: In phase 1, cohort-specific doses of SC nemvaleukin are administered on an every-7-day (q7d) or every-21-day (q21d) schedule during a 6-week monotherapy lead-in period, followed by combination with pembrolizumab 200 mg q21d. We present safety, PD effects, and preliminary clinical activity outcomes as of 12/02/2020. Results: 57 pts received nemvaleukin doses ranging from 0.3 mg to 6 mg q7d or 1 mg to 10 mg q21d. The most frequent tumor types (> 5 pts) were colorectal, pancreatic, ovarian, and lung; median number of prior therapies was 4. Treatment-related adverse events (TRAEs) in > 30% pts overall were pyrexia (43.9%), chills (38.6%), injection site erythema (33.3%), injection site reaction (33.3%), and fatigue (31.6%). 3 mg q7d (n = 7) had no drug-related dose reductions, discontinuations, or deaths during the monotherapy or combination periods. 6 mg was declared the maximum tolerated dose (MTD) for q7d dosing as 2 of 8 pts experienced dose-limiting toxicities (DLTs). For 6 mg q21d (n = 7), no drug-related dose reductions, discontinuations, or deaths have occurred during the monotherapy period; combination period data are not mature. 10 mg was declared the MTD for q21d dosing as 1 of 9 pts experienced DLTs and 3 had TRAEs leading to dose reductions. Systemic exposure to nemvaleukin increased with increasing dose. Increases in NK cells and CD8 ⁺ T cells of approximately 16-fold and 3-fold, respectively, at 3 mg q7d, and approximately 8-fold and 3-fold, respectively, at 6 mg q21d were observed, with minimal change in T _regs. 46 pts had at least 1 on-treatment scan as of the data cutoff date, and 30 (65%) had stable disease (SD) on the first scan. Of the 30 pts with ≥2 scans, 13 (43%) had 2+ consecutive scans of SD. 16 of 57 pts remain on therapy. Antitumor activity data for more recent cohorts are still maturing. Based on the totality of the safety, PD effects, and antitumor activity data, 3 mg q7d was selected as the RP2D for SC nemvaleukin. Conclusions: SC nemvaleukin 3 mg q7d was generally well tolerated as monotherapy and in combination with pembrolizumab, and demonstrated robust PD effects on NK cells and CD8 ⁺ T cells with minimal expansion of T _regs. These PD effects are similar to or greater than those observed with intravenous nemvaleukin. Thus, 3 mg q7d was selected as RP2D; phase 2 expansion cohorts for combination with pembrolizumab are enrolling. Clinical trial information: NCT03861793.