611 Imneskibart + low-dose subcutaneous IL-2 ± nivolumab in doublet checkpoint inhibitor-refractory melanoma: promising activity in an ongoing phase 1/2 study
Year: 2026
Type: conference-abstract
Abstract: Background Imneskibart is a human mAb designed by leveraging AI that binds interleukin-2 (IL-2) and inhibits IL-2’s binding to CD25 in the trimeric IL-2 receptor (IL-2R), while allowing engagement with the dimeric receptor, CD122/CD132. Imneskibart-bound IL-2 expands T effector (Teff) and NK cells, which express dimeric IL-2R, without expanding regulatory T cells (Tregs; trimeric IL-2R).Methods Patients with locally advanced or metastatic cutaneous melanoma having objective progression after ≥2 cycles of prior dual checkpoint inhibitor therapy (CPI: anti–PD-1 plus anti–CTLA-4 or anti–LAG-3), with progression confirmed ≥4 weeks later were enrolled. Patients received either the recommended Phase 2 dose (RP2D) of 9 mg/kg imneskibart IV Q2W, or nivolumab Q4W + the RP2D of imneskibart. Both cohorts received a subcutaneous (SC) 135K IU/kg aldesleukin dose on Day 1 of Cycle 1. An additional aldesleukin dose could be administered at the beginning of each 8-week cycle until at least a partial response (PR) occurred. Tumors were assessed at the end of each 8-week cycle.Results Fourteen evaluable patients received imneskibart + aldesleukin (2 patients treated in Phase 1 received doses < RP2D1). Four patients had reductions of 47%, 48%, 58%, and 100% in target and measurable non-target lesions and remained on treatment for 13–26 months (2 ongoing).Fifteen evaluable patients received nivolumab + imneskibart + aldesleukin. Four patients had reductions of 52%, 65%, 74%, and 77% (3 confirmed PRs, 1 awaiting confirmation). Seven patients had stable disease, yielding a 73% disease control rate. Eight patients continue treatment and one is in post-treatment follow-up. Imneskibart + IL-2 ± nivolumab decreased peripheral Tregs with concomitant CD8+ T-cell increases, producing up to 2–3-fold increases in CD8/Treg ratios versus baseline.Imneskibart + IL-2 was well tolerated with Grade 3/4 drug-related adverse events occurring in 14.5 % of pts and in 10.5% of pts who received the combination with nivolumab. No patient discontinued treatment due to a drug-related event.Conclusions Imneskibart + low dose IL-2 demonstrated clinically meaningful, durable antitumor activity in patients with melanoma who progressed after prior doublet checkpoint inhibitor therapy. Nivolumab addition showed an emerging signal of enhanced efficacy without increasing toxicity beyond that observed with imneskibart + aldesleukin alone. These data suggest imneskibart + low-dose IL-2 ± nivolumab may open a new therapeutic path for patients with doublet CPI-refractory melanoma, a high-need population with no FDA-approved options.Trial Registration NCT05267626Ethics Approval This study was approved by Monash Health (Australia) HREC/80672/MonH-2021-295282(v2) and Advarra IRB (US) CR00561013. All patients provided informed consent prior to enrollment.
Authors: Meredith McKean, Andrew Haydon, Sophia Frentzas, Siwen Hu-Lieskovan, Paul de Souza, John D Powderly, Drew Rasco, Andrew Weickhardt, Ganessan Kichenadasse, Vinod Ganju, Nehal Lakhani, Jose Lutzky, Jeffrey T Yorio, Eric Lander, Timothy L Wyant, Jenny Tang, Lori Richards, Aron Knickerbocker, Yanay Ofran, James R Vasselli
Institutions: Sarah Cannon, The Alfred Hospital, Monash Medical Centre, Monash Health, University of Utah, Carolina BioOncology Institute, South Texas Accelerated Research Therapeutics, Austin Health, Flinders Medical Centre, Start Treatment & Recovery Centers, University of Miami, Sylvester Comprehensive Cancer Center, Texas Oncology, Minnesota Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225325719