Work

605 Imneskibart, a human monoclonal antibody (mAb), + low-dose subcutaneous IL-2 + avelumab: phase 2 promising activity in CPI-refractory adenocarcinoma non-small cell lung cancer (NSCLC)

Year: 2026

Type: conference-abstract

Abstract: Background Patients with metastatic lung adenocarcinoma progressing after chemo-immunotherapy have limited treatment options. Available therapies, including docetaxel ± ramucirumab, typically achieve ORRs of only approximately 10–15% and median overall survival (OS) of approximately 1 year, highlighting a substantial unmet need for more effective and durable treatments. Imneskibart, a human mAb designed by leveraging AI, binds to interleukin-2 (IL-2) on its CD25 epitope. Imneskibart-bound IL-2 cannot bind trimeric (CD25/CD122/CD132) IL-2 receptors (IL-2R) but can engage dimeric (CD122/CD132) IL-2R. This promotes expansion of T effector (Teff) and NK cells, which express dimeric IL-2R, without expanding regulatory T cells (Tregs; trimeric IL-2R). Avelumab is an anti-PD-L1 mAb with an active Fc region that may engage innate and adaptive antitumor immunity.Methods This ongoing Phase 2 expansion cohort enrolls patients with PD-L1-positive (tumor proportion score ≥ 1%) NSCLC whose disease progressed on anti-PD-1/PDL1 ± chemotherapy. Patients receive avelumab 800 mg Q2W + imneskibart 9 mg/kg IV Q2W and one subcutaneous (SC) 135K IU/kg aldesleukin dose on Day 1. Additional SC aldesleukin doses may be administered at the beginning of each cycle until at least a partial response (PR) is obtained. Tumors are assessed at the end of each 8-week cycle.Results Fourteen heavily pre-treated patients (median 2 prior lines of therapy, range 1–6) with adenocarcinoma of the lung that progressed on prior CPI + chemotherapy were assessed per RECIST 1.1. Three patients (21.4%) had a PR (-42%, on treatment at 6 months [M]; -43%, on treatment at 9 M; -45%, 6 M on treatment). Three additional patients had tumor reductions (2 are ongoing treatment) and 11/14 (79%) achieved disease control. Treatment induced durable reductions in peripheral Treg counts below baseline, with concomitant expansion of CD8 + T cells and NK cells, resulting in sustained 2–3-fold increases in CD8/Treg ratios. Emerging data show CD8/Treg ratio increases >2× over baseline are associated with longer treatment duration, progression free survival, and OS. Capillary leak syndrome was not observed.Conclusions Avelumab + imneskibart + low-dose SC IL-2 demonstrated encouraging preliminary anti-tumor activity in patients with lung adenocarcinoma that progressed after prior checkpoint inhibitor-based therapy + chemotherapy. The combination regimen demonstrated a manageable safety profile in the outpatient setting. Pharmacodynamic evidence of Treg reduction and effector immune cell expansion supports further evaluation of this immunomodulatory strategy. Additional efficacy, safety and biomarker analyses are ongoing.Acknowledgements Avelumab was provided by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).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.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0605