nemvaleukin alfa (ALKS 4230)

The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.

P2, N=180, Recruiting, Mural Oncology, Inc | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Mar 2024 --> Jun 2025

P3, N=456, Active, not recruiting, Mural Oncology, Inc | Recruiting --> Active, not recruiting

P1/2, N=78, Active, not recruiting, Mural Oncology, Inc | Recruiting --> Active, not recruiting

P3, N=448, Recruiting, Mural Oncology, Inc | Active, not recruiting --> Recruiting | Trial completion date: Dec 2026 --> May 2027 | Trial primary completion date: Dec 2025 --> May 2026

Our model reproduces differential effects of immunotherapy in melanoma patients, capturing the inherent heterogeneity in clinical responses. Taken together, these data demonstrate our model's translatability for novel immunotherapies in melanoma patients. The data are also supportive for the continued clinical investigation of nemvaleukin as a novel immunotherapeutic for the treatment of melanoma.

P3, N=376, Active, not recruiting, Mural Oncology, Inc | Recruiting --> Active, not recruiting

P1/2, N=243, Completed, Mural Oncology, Inc | Active, not recruiting --> Completed

The primary end point is investigator-assessed progression-free survival. Clinical Trial Registration: GOG-3063; ENGOT-OV68; NCT05092360 (ClinicalTrials.gov).

Patients must have had â¥1 prior line of platinum-based therapy, â¤5 prior lines of systemic anticancer therapy (platinum-resistant setting), and prior bevacizumab, with radiographic progression on most recent therapy...Approximately 376 patients will be randomised (3:1:1:3) to receive nemvaleukin 6 μg/kg IV (days 1-5)+pembrolizumab 200 mg IV (day 1) of each 21-day cycle, pembrolizumab or nemvaleukin monotherapy, or chemotherapy, and stratified by PD-L1 status, histologic subtype, and chemotherapy (paclitaxel vs others)...Primary endpoint: investigator-assessed progression-free survival (RECIST v1.1) with nemvaleukin+pembrolizumab vs chemotherapy. Secondary/exploratory endpoints include overall survival, other antitumor measures, safety, health-related quality of life, and pharmacokinetic/pharmacodynamic effects.Results Trial in progressConclusion Pending data availability

P1/2, N=78, Recruiting, Alkermes, Inc. | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2023 --> Jul 2024

High-dose recombinant human IL-2 (rhIL-2, aldesleukin) emerged as an important treatment option for selected patients with metastatic melanoma and metastatic renal cell carcinoma, producing durable and long-lasting antitumor responses in a small fraction of patients and heralding the potential of cancer immunotherapy...In this review, we highlight novel drug development strategies, including biochemical modifications and engineered IL-2 variants, to expand the narrow therapeutic window of IL-2 by leveraging downstream activation of the IL-2 receptor to selectively expand anti-tumor CD8-positive T cells and natural killer cells. These modified IL-2 cytokines improve single-agent activity in solid tumor malignancies beyond the established United States Food and Drug Administration (FDA) indications of metastatic melanoma and renal cell carcinoma, and may also be safer in rational combinations with established treatment modalities, including anti-PD-(L)1 and anti-CTLA-4 immunotherapy, chemotherapies, and targeted therapy approaches.

Trial in progress.

MC38 tumor-bearing C57Bl/6 mice were subcutaneously administered murine nemvaleukin alfa (mNemva), an engineered IL-2 immunotherapy that selectively activates and expands cytotoxic NK cells and antigen-experienced CD8+ T cells. Moreover, long-term immunity was 100% effective if the re-challenge experiment was performed out to 5 months after the last dose of mNemva had been administered.Therefore, the neoadjuvant/adjuvant dosing regimen exhibits a superior response in this preclinical model, when combined with partial tumor-debulking surgery, similar to the recent findings in patients with melanoma that were treated with pembrolizumab. In addition, this strategy enables sampling of tumor tissue for analyses of the immune response and the identification of potential predictive markers of response.

In this all autologous humanized melanoma mouse model, nemvaleukin treatment not only enhances T cell engraftment, it significantly augments anti-tumor efficacy. These data support the use of this personalized melanoma xenograft model to analyze the underlying immune responses in responders and non-responders to novel immunotherapies.

P2, N=176, Recruiting, Alkermes, Inc. | N=110 --> 176

mNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.

Patients must have had ≥1 prior line of systemic therapy (platinum-sensitive setting), ≤5 prior lines (platinum-resistant setting), and prior bevacizumab, with radiographic progression on most recent therapy. Trial in progress: there are no available conclusions at the time of submission

Nemvaleukin alfa, an engineered cytokine that may induce the tumor-fighting benefits of IL2 without the side effects, has demonstrated effectiveness against solid tumors. As a monotherapy, the drug produced overall response rates of 13% in patients with advanced melanoma and 18.2% in advanced renal cell carcinoma. When combined with pembrolizumab, the drug produced responses in 16.1% of patients with various solid tumor types.

The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD-1 or adoptive T cell therapy.

P1/2, N=78, Recruiting, Alkermes, Inc. | Phase classification: P2 --> P1/2 | N=36 --> 78 | Trial completion date: Mar 2022 --> Mar 2024 | Trial primary completion date: Mar 2022 --> Mar 2023

Emerging data from pretreatment and on-treatment paired biopsies will further characterize specific antitumor effects of nemvaleukin and pembrolizumab in this patient population. Trial Registration ClinicalTrials.gov NCT04144517

The primary endpoint is the response rate (RECIST v1.1) to ALKS 4230 + pembrolizumab in patients with ≥ 8 weeks of prior anti-PD-1/L1 therapy and with stable disease or partial response (Group 1) or progressive disease (Group 2). Secondary endpoints are the duration of response, progression-free survival, time to progression, overall survival, and safety/tolerability.

After confirming tumor burden by magnetic resonance imaging (MRI), mice were treated with RDB 1462 alone or in combination with standard chemotherapy (cisplatin + etoposide). The mouse version of nemvaleukin, RDB 1462, demonstrated anti-tumor immunity in a murine model of SCLC. RDB 1462 reduced SCLC growth and prolonged survival in mice, which was further enhanced by combining with standard chemotherapy. The data could potentially support further evaluation of nemvaleukin in the treatment of SCLC either alone or in combination in the clinic.

P2, N=110, Recruiting, Alkermes, Inc. | Not yet recruiting --> Recruiting

Both patients had received prior nivolumab adjuvant therapy and had relapsed 8-9 months after completing nivolumab therapy. Nemvaleukin is a novel, investigational agent that is generally well tolerated, has demonstrated antitumor activity, and can be administered in an outpatient setting. Single-agent activity was observed among patients with melanoma who were previously treated with a CPI. Response criteria were met to expand the monotherapy melanoma cohort, and research of nemvaleukin among patients with advanced melanoma is ongoing.

P2, N=110, Not yet recruiting, Alkermes, Inc.

P2, N=36, Recruiting, Alkermes, Inc.

One pt with metastatic urethral melanoma (which had previously recurred following adjuvant nivolumab) achieved partial response (PR) to 6 μg/kg ALKS 4230 monotherapy with normalization of serum LDH. Funding: Alkermes, Inc. Clinical trial identification: NCT02799095.

ALKS 4230, an engineered cytokine designed for selective binding to the intermediate affinity interleukin-2 receptor (IL-2R), is being evaluated as a monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. The combination led to a significant (p<0.05) increase in intratumoral CD8+ T cells and dendritic cells (CD11c+F4/80-), together with a reduction in tumor-associated macrophages (CD11b+F4/80+). The combination treatment elicited a distinct gene expression profile in tumors by RNA-Seq, merging the immunostimulatory effects of RDB 1462 with the anti-angiogenic effects of lucitanib.The combination of an intermediate affinity IL-2R-selective cytokine and an angiogenesis inhibitor resulted in durable dose-dependent antitumor efficacy in the MC38 mouse tumor model.

ALKS 4230 exhibited enhanced pharmacokinetic and selective pharmacodynamic properties resulting in both improved antitumor efficacy and lower indices of toxicity relative to rhIL-2 in mice. These data highlight the potential of ALKS 4230 as a novel cancer immunotherapy, and as such, the molecule is being evaluated clinically.

P1/2, N=257, Ongoing, Alkermes, Inc.