A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors: Dose escalation study

Abstract Background: IO-108 is a fully human IgG4 monoclonal antibody with high affinity and specificity towards LILRB2 (also known as ILT4). It blocks the interaction of LILRB2 with the known ligands for LILRB2, including HLA-G, ANGPTLs, SEMA4A and CD1d. Methods: IO-108-CL-001 is a first-in-human, Phase 1a/1b study in patients with relapsed/refractory solid tumors (NCT05054348). The dose escalation phase enrolled patients into escalating dose cohorts of IO-108 (60-1800 mg, Q3W IV) as monotherapy or in combination with pembrolizumab. Patients with disease progression on monotherapy could crossover to the combination arm. Primary objectives were safety and tolerability, and identification of the recommended phase 2 dose (RP2D). Secondary and exploratory objectives include evaluation of pharmacokinetics (PK), immunogenicity, pharmacodynamic (PD) biomarker effects and anti-tumor activity as measured by objective response rate (RECIST 1.1). Results: Twenty-five relapsed/refractory solid tumor patients (median 4.5 prior lines of therapy for monotherapy and 3.6 for combination therapy) were treated with IO-108 monotherapy (n=12) or IO-108 + pembrolizumab (n=13). IO-108 was well-tolerated up to the maximal administered dose of 1800 mg Q3W as monotherapy and in combination with pembrolizumab, with no SAEs related to IO-108 and no DLTs observed. Maximum tolerated dose (MTD) was not reached. Full receptor occupancy through 21 days was achieved at ≥600 mg. The preliminary RP2D is 1200 mg Q3W. Dose-expansion cohorts of IO-108 monotherapy and IO-108 + anti-PD-1 are ongoing.Twenty-three patients were efficacy evaluable (11 monotherapy, 12 combination therapy plus 1 crossover). Overall response rate was 9% in monotherapy cohort (1 Merkel cell carcinoma, prior pembrolizumab followed by nivolumab/ipilimumab) and 23% in combination therapy (2 cholangiocarcinoma, 1 MSS CRC with neuroendocrine features)​. The best overall response was 1 CR, 4 SD among monotherapy, and was 3 PR, 4 SD among combination therapy.​ The 4 responding patients remain on study with an on-going treatment duration of 8 to 12 months as of abstract submission.Consistent with the MOA, clinical benefit correlated with baseline characteristics and post-treatment changes in PD biomarkers including reprogramming of myeloid cells and activation of T cells. Conclusion: The initial encouraging data support further development of IO-108, both as monotherapy and in combination with anti-PD-(L)1 for patients with advanced solid tumors. Citation Format: Matthew H. Taylor, Manish R. Patel, John D. Powderly, Paul Woodard, Luke Chung, Hongyu Tian, Xiang Hong, Kyu Hong, Donna Valencia, Tao Huang, Xiao Min Schebye, Charlene Liao, Aung Naing. A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors: Dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT040.