Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8⁺ T and NK cells, with minimal expansion of T_regs. Nemvaleukin is under investigation for the treatment of advanced solid tumors, including renal cell carcinoma (RCC), in the ARTISTRY-1 trial (NCT02799095). Demonstration of single-agent activity is essential to validate the potential therapeutic benefit of nemvaleukin, both as monotherapy and in combination with a checkpoint inhibitor (CPI), particularly in patients (pts) with limited treatment options, such as CPI-experienced pts with RCC. Methods: Pts with advanced RCC who had previously responded (either objective response or stable disease [SD]) to a CPI alone or as part of a combination were enrolled into an RCC-specific cohort of ARTISTRY-1 Part B. Nemvaleukin 6 µg/kg IV monotherapy was administered daily for 5 days every 14 days in cycle 1 and every 21 days in cycles 2+. Pts with disease progression (PD; after ≥2 cycles) or SD (after ≥4 cycles) could be enrolled into Part C to receive nemvaleukin and pembrolizumab combination therapy. Outcomes presented include antitumor activity (RECIST v1.1), pharmacodynamics, and safety as of August 2021. Results: Twenty-seven pts with RCC received nemvaleukin monotherapy in Part B. Median age was 69 y (range, 39-77); median prior lines of therapy was 2 (range, 1-7). Four of 21 evaluable pts had a best overall response of partial response (1 confirmed, 1 unconfirmed, 2 awaiting confirmation); 11 had SD. Nemvaleukin induced robust expansion of CD8⁺ T and NK cells with minimal effect on T_regs. The most frequently reported adverse events (AEs), regardless of causality (N = 27), were pyrexia (59.3%), chills (55.6%), nausea (29.6%), and anemia (29.6%). The most frequently reported grade ≥3 nemvaleukin-related AEs are shown in the table. One pt had an AE (nemvaleukin-related bronchospasm) resulting in treatment discontinuation. There were no deaths due to treatment-related AEs. Four pts are continuing monotherapy in Part B (up to 1 y) and 10 have rolled over to Part C (combination therapy). Of the 8 evaluable pts with PD on Part B who subsequently received combination therapy in Part C, 1 had a confirmed partial response and has now been on treatment for almost 1 y and 5 had SD. No additional safety signals were observed. Conclusions: Nemvaleukin was generally well tolerated as monotherapy and in combination with pembrolizumab, and provided evidence of single-agent tumor response and disease control in CPI-experienced pts with advanced RCC. Clinical evaluation of nemvaleukin among pts with advanced RCC is ongoing. Clinical trial information: NCT02799095.