Nemvaleukin Alfa Demonstrates Durable Disease Control in Advanced Melanoma and RCC

Nemvaleukin alfa monotherapy demonstrated modest antitumor activity and durable disease control in patients with advanced melanoma or renal cell carcinoma (RCC), according to findings from the phase 1/2 non-randomized ARTISTRY-1 trial (NCT02799095).

Findings published in the Journal for Immunotherapy of Cancer showed that from July 2016 to March 2023, 74 patients enrolled in part B of the study received nemvaleukin alfa monotherapy (melanoma, n = 47; RCC, n = 27). In the melanoma cohort, the objective response rate (ORR) was 9% (95% CI, 2%-21%), and the disease control rate (DCR) was 50% (95% CI, 35%-65%). Stable disease persisted for at least 6 months in 7% of patients.

In the RCC cohort, the ORR was 14% (95% CI, 3%-35%), and the DCR was 50% (95% CI, 28%-72%); 9% of patients achieved stable disease for longer than 6 months.

The most common grade 3/4 nemvaleukin alfa–related treatment-emergent adverse effect (TEAE) was neutropenia, reported in 57% of patients with melanoma and 33% of patients with RCC. No patients in either cohort experienced grade 3 or higher cytokine release syndrome (CRS) or infusion-related reactions, and there were no reported cases of capillary leak syndrome or febrile neutropenia.

“Nemvaleukin [alfa] demonstrated pharmacodynamic proof of mechanism, with single-agent antitumor activity and manageable safety in patients with advanced melanoma and RCC,” lead study author Emiliano Calvo, MD, PhD, director of Clinical Research at START Madrid-CIOCC and START Madrid-FJD in Spain, and colleagues wrote in the publication of the data.

ARTISTRY-1 Trial Breakdown

The phase 1/2 ARTISTRY-1 trial was a global, multicenter, open-label study conducted across 32 sites in 7 countries. The trial comprised three parts: part A (dose-escalation monotherapy), part B (dose-expansion monotherapy), and part C (nemvaleukin alfa in combination with pembrolizumab [Keytruda]).

Eligible patients for part B were at least 18 years of age, had an ECOG performance status of 0 or 1, and had at least one measurable target lesion per RECIST 1.1 criteria.

The melanoma cohort included patients who had received prior immune checkpoint inhibitor (ICI) therapy with or without anti–CTLA-4 therapy, and, when appropriate, molecularly targeted therapy. Patients could have received no more than one prior cytotoxic chemotherapy regimen. In the RCC cohort, enrollment was permitted regardless of prior ICI exposure, provided patients with prior anti–PD-(L)1 treatment had received no more than 2 prior systemic regimens, including the ICI-containing regimen.

Patients were required to have achieved at least stable disease or better with prior ICI therapy unless approved for enrollment on a case-by-case basis by the medical monitor. Key exclusion criteria included active autoimmune disease requiring systemic therapy within 3 months, history of severe autoimmune disease necessitating systemic immunosuppression, or prior IL-2– or IL-15–based therapy.

In part B, nemvaleukin alfa was administered at the recommended phase 2 dose of 6 µg/kg once daily on days 1-5 of each cycle. Cycle 1 lasted 14 days, with 9 days off treatment; subsequent cycles were 21 days, with 16 days off treatment.

Primary objectives for part B were ORR per RECIST 1.1 criteria and to characterize the safety profile, including incidence and severity of TEAEs. Secondary objectives included evaluating pharmacokinetics, antidrug antibody incidence, DCR, duration of response, progression-free survival, and changes in peripheral immune cell subsets, including CD8-positive T cells, regulatory T cells, and natural killer cells.

Patient Demographics

In part B of the ARTISTRY-1 trial, the median age was 66 years (range, 37-82) for patients in the melanoma cohort and 69 years (range, 39-77) for those in the RCC cohort. Males comprised 53% of the melanoma cohort and 89% of the RCC cohort. Most patients were White (melanoma, 89%; RCC, 93%), with smaller proportions identifying as Asian (11%; 4%) or Black/African American (0%; 4%).

Performance status was evenly distributed in the melanoma group, with 49% having an ECOG performance status of 0 and 51% having a score of 1. In contrast, the RCC cohort, 26% had an ECOG performance status of 0, and 74% had a score of 1. Patients were heavily pretreated, with a median of 3 prior lines of therapy (range, 1-8) in the melanoma cohort and 2 (range, 1-8) in the RCC cohort.

Prior ICI exposure was common, with anti–PD-1 therapy received by 96% of patients with melanoma and 56% of patients with RCC; prior anti–PD-L1 therapy was given to 6% and 7% of patients, respectively; anti–CTLA-4 therapy was received by 36% and 15%, respectively; and combination anti–PD-1 plus anti–CTLA-4 therapy was administered to 6% and 4%, respectively.

Among the melanoma cohort, 40% had baseline lactate dehydrogenase (LDH) levels above normal, with a median of 438 U/L (range, 233-1921 U/L); 60% had levels within normal limits. In the RCC cohort, 74% had clear cell histology, with the remainder having variants including clear cell and oncocytoma (n = 1), clear cell and non–clear cell (n = 1), and clear cell with rhabdoid features (n = 1).

Safety and Pharmacokinetic/Pharmacodynamic Findings

In part B, patients with advanced melanoma or RCC received a median of six treatment cycles, corresponding to a median treatment duration of 14.7 weeks in both cohorts. Relative dose intensity was high, with a median of 98% in each group. Rates of dose interruptions and dose reductions were similar between cohorts.

Nearly all patients experienced at least one nemvaleukin alfa–related treatment-related AE (TRAE), with incidences of 96% in the melanoma cohort and 100% in the RCC cohort. Grade 3 or 4 TRAEs occurred in 77% and 74% of patients, respectively. In the melanoma group, the most common TRAEs of any grade reported in at least 25% of patients included fever (68%), nausea (47%), and neutropenia (47%), whereas in RCC, these were fever (59%), chills (52%), and neutropenia (41%). Neutropenia was the most frequent grade 3/4 TRAE, reported in 57% of patients with melanoma and 33% of patients with RCC.

Nemvaleukin alfa–related serious AEs were observed in 15% of patients with melanoma and 30% of patients with RCC. Infusion-related reactions occurred in 2% and 15% of patients, respectively, while CRS was reported in 2% of patients with melanoma. Filgrastim was used in 5% of patients for neutropenia management.

TRAEs leading to treatment discontinuation were uncommon (4% in melanoma; 4% in RCC). One death due to COVID-19 occurred in the RCC cohort and was deemed unrelated to treatment.

Pharmacokinetic analyses demonstrated similar nemvaleukin alfa exposure between cohorts. Following the first intravenous infusion at 6 µg/kg, peak serum concentrations were reached at approximately 0.5 hours post infusion—106 ng/mL in melanoma and 132 ng/mL in RCC—and declined slowly in a monophasic pattern, remaining detectable at 24 hours post-dose. Trough concentrations decreased from cycle 1, day 2 to cycle 1, day 5, with stabilization during cycle 2, suggesting achievement of steady state by cycle 2, day 2. Area under the concentration-time curves and time to last quantifiable concentration were comparable across cohorts.

“Overall, nemvaleukin [alfa] demonstrated preliminary antitumor activity in patients with advanced melanoma and RCC, along with a manageable safety profile, and selective activation of the proinflammatory immune pathways, supporting its potential as an active and tolerable cytokine therapy,” said Calvo. “Future research should focus on identifying optimal patient subsets, tumor types, and combination strategies to maximize the therapeutic benefit.”

Reference

Calvo E, Boni V, Dumas O, et al. Nemvaleukin alfa monotherapy in patients with advanced melanoma and renal cell carcinoma: results from the phase 1/2 non-randomized ARTISTRY-1 trial. J Immunother Cancer. 2025;13(8):e010777. doi:10.1136/jitc-2024-010777