Abstract 3641: Pharmacodynamic and predictive biomarker results from the phase I dose escalation study of NGM707, an ILT2/ILT4 dual antagonist antibody, in patients with advanced solid tumors
Authors: Blum Lisa K. , Chen Hung-I H. , De Costa Anushka , Iyer Anjushree , Stone Geoffrey W. , Galicia Nicole D. , Chan Jerry , Dampier Brenda , Wu Katherine , Jeffry Ursula , Zhou Kefei , Sloan-Lancaster Joanne , Abhayankar Dhiraj , Hanes Vladimir , Lieu Hsiao D. , Kaplan Daniel D. , Roda Julie M. 
Published: March 2024

Background: NGM707 is a dual antagonist antibody that binds a shared epitope of the immune inhibitory receptors ILT2 (LILRB1) and ILT4 (LILRB2). In preclinical studies, NGM707 reprogrammed suppressive myeloid cells via blockade of ILT2/ILT4 and enhanced NK and CD8+ T cell activity via blockade of ILT2; furthermore, NGM707 and pembrolizumab acted additively in vitro to enhance CD4+ T cell activation in mixed lymphocyte reactions. NGM707-IO-101 (NCT04913337) is a first-in-human Phase 1/2 clinical trial of NGM707 monotherapy and combination with pembrolizumab. Here we report pharmacodynamic and predictive biomarker data from NGM707-IO-101 monotherapy and combination dose escalation cohorts.

Methods: Eligible patients with advanced or metastatic solid tumors were enrolled into escalating dose cohorts from 6 to 1800 mg NGM707, alone or in combination with 200 mg pembrolizumab, administered Q3W iv. Biomarker assessments of tumors comprised RNA-sequencing and immunohistochemistry (including ILT2, ILT4, CD163) of archival/baseline (N= 41 IHC, 47 RNA) and paired on-treatment tumor biopsies (N=13 IHC, 21 RNA). Peripheral blood biomarker samples were collected on days 1, 4, 8, and 15 of cycle 1 and prior to dosing at each subsequent cycle. Blood biomarker assessments included circulating cytokines/chemokines, PBMC RNA-sequencing, and flow cytometry immunophenotyping. Baseline biomarkers were associated with anti-tumor activity per RECIST v1.1.

Results: Pre-treatment biopsies from patients with disease control (DC) showed higher expression of genes in the 18-gene tumor inflammation signature (TIS) than patients with progressive disease (PD). A composite gene signature incorporating gene sets related to TIS, NK cell activity, and tumor cell proliferation had a statistically stronger association with DC than TIS genes alone. Baseline ILT2/ILT4 target expression (≥1% of tumor area) was observed in 31 (75.6%) patients, with similar levels observed in patients with DC and PD. Pharmacodynamic changes were observed in tumor samples following treatment, including increased expression of gene signatures that reflect myeloid cell activation and a proinflammatory tumor microenvironment. Decreased protein expression of the immunosuppressive myeloid marker CD163 was observed following treatment in both blood and tumor for a subset of patients. Proinflammatory chemokines including CXCL9 increased in serum following treatment.

Conclusion: Baseline gene expression signatures have shown an encouraging association with clinical benefit from NGM707 and merit further investigation as promising predictive biomarkers. Protein and gene expression changes reflecting the expected modes of action of NGM707 and pembrolizumab were observed in both peripheral blood and tumor biopsies following treatment.

Citation Format: Lisa K. Blum, Hung-I H. Chen, Anushka De Costa, Anjushree Iyer, Geoffrey W. Stone, Nicole D. Galicia, Jerry Chan, Brenda Dampier, Katherine Wu, Ursula Jeffry, Kefei Zhou, Joanne Sloan-Lancaster, Dhiraj Abhayankar, Vladimir Hanes, Hsiao D. Lieu, Daniel D. Kaplan, Julie M. Roda. Pharmacodynamic and predictive biomarker results from the phase I dose escalation study of NGM707, an ILT2/ILT4 dual antagonist antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3641.