8556 Background: ILKN421H is an LNP mRNA encoding an IL2Rβγ selective IL-2v derivative fused with Human Serum Album. Preclinically, the novel LNP mRNA platform allowed expression and therefore extended plasma half-life of IL2v in animal models, which is not achieved with other protein-based IL-2 drugs. ILKN421H stimulated significant and sustained expansion of CD8 T cells for more than three weeks, with minimal expansion of regulatory T cells. Moreover, ILKN421H demonstrated superior efficacy than IL-2 based drugs in multiple cancer models and has an excellent safety profile in rodents and non-human primates. Therefore, the novel design of ILKN421H has the potential to fully unleash the antitumor effects of the IL-2 pathway while mitigating unwanted toxicity. Methods: This first-in-human, open label phase 1 study evaluates the safety, tolerability, and initial efficacy of ILKN421H with or without pembrolizumab in patients with advanced solid tumors. The design includes two portions of the study: Parts A, ILKN421H monotherapy in which patients receive intravenous ILKN421H once every 3 weeks (Q3W) and Part B in which patients receive ILKN421H in combination with pembrolizumab (200 mg on day 1), both intravenous Q3W. Both portions of the study consist of 3+3 escalation cohorts to define maximum tolerated dose (MTD). If response signal is observed in a given dose cohort, additional 10 patients will be enrolled in the expansion portion of the study to further evaluate the safety and efficacy. The trial is ongoing and data as of 5/7/2024 is presented in this abstract. Results: A total of 47 participants were enrolled so far. In Part A, 9 patients in three dose cohorts received ILKN421H. All patients demonstrated high and prolonged plasma level of IL-2, and remarkable elevation of CD8 T cells (up to 5 folds) and NK cells (up to 25 folds). No dose-limiting toxicities (DLT) were observed. In Part B, 38 patients in three dose cohorts were enrolled, 24 of which are 1L advanced NSCLC. All patients showed robustly increased CD8 T cells and NK cells, and well tolerated safety profile (TESAE=26%). At the cut-off date (Nov 25th, 2025), of the 22 efficacy evaluable 1L NSCLC patients regardless of the PDL1 expression levels, 17 were evaluated to be PR (ORR=77.2%), and 50% PFS was not reached and was projected to be more than 14 month. In PDL1 negative patients (TPS <1%), 3 out of 6 patients achieved PR (ORR=50%). Conclusions: ILKN421H was generally well tolerated at the current dose level, which already demonstrated high and prolonged plasma level of IL-2, and robust immune stimulatory activity in promoting CD8 T cells and NK cells proliferation. Initial signs of antitumor efficacy were seen in combination with pembrolizumab. Clinical trial information: NCT05978102 .
Wang et al. (Thu,) studied this question.