Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1.

Abstract

2500 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 (IL-2) receptor (IL-2R) to preferentially activate antitumor CD8+ T cells and natural killer (NK) cells with minimal expansion of immunosuppressive regulatory T cells. It is sterically occluded from binding to the high-affinity IL-2R, leveraging antitumor effects of the IL-2 pathway but mitigating toxicity associated with preferential binding of IL-2 to the high-affinity IL-2R. Methods: ARTISTRY-1 (NCT02799095) is a 3-part, first-in-human, phase 1/2 study of IV nemvaleukin alone and in combination with pembrolizumab in pts with advanced solid tumors. Parts A (dose escalation to 10 µg/kg/day), B (monotherapy in pts with melanoma or renal cell carcinoma [RCC]), and C (combination) included nemvaleukin 3 or 6 µg/kg/day ´ 5 and pembrolizumab every 21 days. Investigator-assessed antitumor activity (confirmed responses as per RECIST v1.1) and safety are reported as of 29 October 2021. Results: In Part A (N = 46), nemvaleukin recommended phase 2 dose was 6 µg/kg/day IV; maximum tolerated dose not reached. One pt had dose-limiting toxicity (grade 4 acute kidney injury) at 10 µg/kg. Pts in Parts B and C were heavily pretreated (1–9 prior lines of therapy, including prior checkpoint inhibitor therapy). Durable antitumor activity was observed for nemvaleukin monotherapy, including in RCC (objective response rate [ORR], 18.2% [4/22]) and in melanoma (ORR, 8.7% [4/46]), with 2 partial responses (1 unconfirmed) in 30 pts with cutaneous melanoma (ORR, 6.7%) and 2 PRs (1 unconfirmed) in 6 pts with mucosal melanoma (ORR, 33.3%). Durable antitumor activity was also observed for combination therapy (ORR, 16.1% [22/137]; disease control rate [DCR], 59.9%), including in platinum-resistant ovarian cancer (PROC; ORR, 28.6% [4/14]; DCR, 71.4%), with 2 complete responses and 2 PRs (1 unconfirmed) in 14 pts. Forty-three pts remain on therapy. The most frequent grade 3/4 treatment-related adverse events in Parts B and C, respectively, were anemia (9%, 10%), neutropenia (34%, 9%), and decreased neutrophil count (12%, 9%). Safety was consistent with previous reports. In pharmacodynamic studies, nemvaleukin monotherapy induced robust expansion of CD8+ T and NK cells, with minimal effect on regulatory T cells. Conclusions: ARTISTRY-1 showed proof of principle for preferential expansion of CD8+ T cells and NK cells by nemvaleukin. Nemvaleukin was generally well tolerated and demonstrated promising efficacy. Durable responses were observed with monotherapy and combination therapy in heavily pretreated pts across a range of tumors, warranting further investigation. The US FDA granted nemvaleukin Fast Track designation for treatment of mucosal melanoma and PROC, and Orphan Drug designation for mucosal melanoma. Clinical trial information: NCT02799095.

Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing

“…Noteworthy partial responses were also noted in patients with platinum-resistant ovarian cancer, alongside instances of stable disease across various other cancers. These initial findings suggest that nemvaleukin alfa may offer advantages over other IL-2 variants [89,90].…”

Is There a Current Role for Combination Chemotherapy or High-Dose Interleukin 2 in Melanoma?

“…Nemvaleukin monotherapy demonstrated durable antitumor activity in melanoma with an ORR of 8.7%. 59 The Cancer Journal • Volume 30, Number 2, March/April 2024…”

“…Toxicity is mitigated because it does not bind the high-affinity IL-2R. Nemvaleukin monotherapy demonstrated durable antitumor activity in melanoma with an ORR of 8.7% 59 …”

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“…There are at least 18 ongoing trials testing immunotherapies, with a multitude of immune-therapeutic targets for PROC. Nemvaleukin alfa is an engineered cytokine that selectively binds to IL-R2 to activate CD8 + T cells and natural killer cells, demonstrating an ORR of 28.6% and disease control rate of 71.4% in a recent trial . A phase 3 RCT, ARTISTRY-7, of nemvaleukin alfa plus pembrolizumab in patients with PROC is currently under way (NCT05092360).…”