Abstract CT047: Interim results from the phase 1/2 ABILITY-1 study of a long-acting ‘beta-enhanced not-alpha’ IL-2 superkine in patients with advanced solid tumors
Authors: Victoria G. Atkinson, Warren Brenner, Jacqueline T. Brown, Luis Cabezón-Gutiérrez, Pablo Gajate, Seung T. Kim, Jenny Lee, Charlotte Lemech, Kim A. Margolin, Irene Moreno, Victor Moreno, Do-Youn Oh, Isabella Glitza Oliva, John J. Park, Hong Shue, Przemyslaw Twardowski, Ira Winer, Michael J. Chisamore, Amy Prawira, Fahar Merchant, Melissa Coello, Minh D. To, Rosemina Merchant, Arash Yavari, Paolo A. Ascierto
Journal: Cancer Research (2025)

Abstract Background: MDNA11 is an engineered IL-2 agonist fused with human albumin that preferentially stimulates CD8+ T and NK cells with minimal effect on immune-suppressive Tregs. The ABILITY-1 (A Beta-only IL-2 ImmunoTherapY) study evaluates the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of MDNA11, both as single agent and in combination with pembrolizumab, in heavily pre-treated patients with advanced solid tumors. We present updated interim safety, PK, PD and efficacy data from the monotherapy portion of the ABILITY-1 study. Method: The monotherapy dose escalation/evaluation portion of the ABILITY-1 study (NCT05086692) uses a modified 3+3 design. Schedule 1 (IV Q2W) at 3, 10, 30, 60, 90 and 120 μg/kg is complete; enrollment to schedule 2 (IV Q3W) is ongoing at the 120 μg/kg dose level. Step-up dosing (SUD) was implemented at doses ≥60 μg/kg across both schedules. Monotherapy dose expansion with IV Q2W at 90 μg/kg (OBD) is currently enrolling selected tumor indications. Primary endpoints were to evaluate safety and tolerability including dose-limiting toxicity (DLT), with secondary endpoint of anti-tumor activity assessed by RECIST 1.1 and iRECIST. Results: As of November 18, 2024, 30 patients have enrolled in monotherapy dose-escalation/evaluation on schedule 1: 16 melanoma, 3 NSCLC, 3 PDAC, 2 RCC, 2 sarcoma, 2 ovarian cancer, 1 tonsillar squamous cell carcinoma and 1 gastro-esophageal adenocarcinoma. No protocol-defined DLTs were observed. The majority of treatment-related adverse events were grade 1-2 and transient, resolving within 72 hours. PK analysis showed dose-dependent increase in exposure. Robust and durable lymphocyte expansion without eosinophilia (associated with vascular leak syndrome) was observed following each dose administration. At data cut off, 12 patients have been enrolled in monotherapy dose expansion, including melanoma (n=4), non-melanoma skin cancer (n=4) and MSI-H/dMMR tumors (n=3). Objective response was achieved in 5 of 20 monotherapy efficacy-evaluable patients treated with MDNA11 ≥60 μg/kg in the phase 2 eligible population who had progressed on immune checkpoint inhibitors (ICI) [ORR of 25%; 95% CI (6-44)], with 1 confirmed complete response (CR: melanoma, continuing on study) and 4 partial responses (PR: 2 MSI-H PDAC and 2 melanoma). Six patients had best response of stable disease, including 3 with duration &amp;gt;6 months (clinical benefit rate of 40%). Analysis of specific immune effector cells is ongoing to further understand mechanism and correlate with response. Conclusions: MDNA11 shows a favorable tolerability profile with no DLTs observed up to 120 μg/kg Q2W. Robust evidence of single agent clinical activity include 1 confirmed CR and 4 PR in patients who had progressed on ICI. Monotherapy dose expansion and combination dose escalation with pembrolizumab continue to enrol. Citation Format: Victoria G. Atkinson, Warren Brenner, Jacqueline T. Brown, Luis Cabezón-Gutiérrez, Pablo Gajate, Seung T. Kim, Jenny Lee, Charlotte Lemech, Kim A. Margolin, Irene Moreno, Victor Moreno, Do-Youn Oh, Isabella Glitza Oliva, John J. Park, Hong Shue, Przemyslaw Twardowski, Ira Winer, Michael J. Chisamore, Amy Prawira, Fahar Merchant, Melissa Coello, Minh D. To, Rosemina Merchant, Arash Yavari, Paolo A. Ascierto. Interim results from the phase 1/2 ABILITY-1 study of a long-acting ‘beta-enhanced not-alpha’ IL-2 superkine in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT047.