Imneskibart + low-dose subcutaneous IL-2 ± nivolumab in patients with CPI-refractory cutaneous melanoma: Promising results from an ongoing phase 1/2 study.

Abstract

9526 Background: Imneskibart (AU-007) is an AI designed monoclonal antibody binding to interleukin-2 (IL-2) preventing binding to CD25 in the trimeric IL-2 receptor (IL-2 R), while allowing engagement with the dimeric IL-2R, CD122/CD132. Imneskibart-bound IL-2 expands T effector (Teff) and NK cell populations (dimeric IL-2R) without expanding regulatory T cells (Tregs; trimeric IL-2R). Methods: Patients (pts) with locally advanced/metastatic cutaneous melanoma were evaluated in Phase 1 (Ph1) dose escalation and in 2 ongoing Ph2 expansion cohorts. Rigorous eligibility criteria were applied requiring pts to have objective progression after ≥ 2 cycles of prior doublet checkpoint inhibitors (CPI, anti-PD-1 + anti-CTLA-4 or anti-LAG-3) with confirmation of progression ≥ 4 weeks later. Ph2 Cohort 1 evaluated the recommended Ph2 dose (RP2D) of 9 mg/kg imneskibart IV Q2W. Ph 2 Cohort 2 evaluates the RP2D of imneskibart IV Q2W + nivolumab (nivo) 480 mg Q4W. Both cohorts receive subcutaneous (SC) 135K IU/kg aldesleukin dose on Day 1 of first cycle with additional doses of aldesleukin administered at the beginning of each cycle until at least a partial response (PR) is obtained. Tumor reassessment is performed at the end of each 8-week cycle. Results: Fifteen pts received imneskibart + aldesleukin: 2 in Ph1 and 13 in Ph2. Fourteen pts were efficacy evaluable. Nine pts had tumor reductions ranging from -1 to -100% including pts with -100% and -58% reductions (continue treatment at 24 and 18 M respectively), and a -48% reduction (14 M on treatment). The median PFS and duration on treatment were 7.6 and 9 M respectively (9.3 M median follow up); 6 pts continue treatment. Nine of 14 evaluable pts have received imneskibart + IL-2 for a longer duration than their prior CPI doublet therapy. Eight pts enrolled in Ph2 Cohort 2 and 2 of the 6 efficacy evaluable pts to date (33%) had PRs with -35% and -31% tumor reductions and continue treatment. Two of 6 had SD and continue treatment. Overall, 67% had disease control at 4 months. Six pts continue treatment. Imneskibart led to a decrease in peripheral Tregs and increase in CD8 cells leading to CD8/Treg ratio increases up to 2 – 3 fold over BL. CD8/Treg ratio increases > 2 fold over BL were associated with longer median duration on treatment, PFS, and OS. Imneskibart + IL-2 was well-tolerated with Grade 3/4 drug-related adverse events (AE) occurring in only 14% of pts and in 0 of the 8 pts who received this combination + nivo. No patient discontinued treatment due to a drug-related AE. Conclusions: Compelling anti-tumor activity is observed with imneskibart + IL-2, with a strong emerging signal of enhanced activity with the nivolumab combination in pts with melanoma refractory to doublet CPI therapy. Imneskibart + IL-2–associated Treg reduction likely drives the high disease control rate, supporting durable benefit with prolonged treatment exposure and PFS. Clinical trial information: NCT05267626 .