Abstract 5181: Early activity and biomarker evaluation of NT219 in combination with cetuximab in a Phase 1/2 study of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)
Authors: Rosenberg Ari J. , Kato Shumei , Johnson Daniel , Popovtzer Aron , Chiu Vi K. , Geva Ravit , Ben-David Hava , Meirson Tomer , Schickler Michael , Reuveni Hadas 
Published: March 2024

Abstract
Background. NT219 is a novel small molecule, dual inhibitor, that uniquely triggers the degradation of Insulin Receptor Substrates 1/2 (IRS) and the dephosphorylation and suppression of STAT3. These two major oncogenic targets in the tumor and tumor microenvironment (TME) play a key role in drug resistance, particularly to EGFR inhibitors. Previously, we demonstrated synergistic effect of NT219 and cetuximab in multiple SCCHN patient-derived xenograft (PDX) models. HPV-negative R/M SCCHN patients have poor survival and demonstrate IGF1R/IRS and STAT3 upregulation. We report biomarker results from dose escalation of NT219 in combination with cetuximab in patients (pts) with immunotherapy-refractory R/M SCCHN (NCT04474470).
Method. Biopsies from 11 enrolled SCCHN patients treated with different dose levels of NT219 (6, 12, 24 and 50 mg/kg) were obtained and evaluated using Immunohistochemistry and pathological analysis. Evaluation of potential biomarkers included measurements of IRS1/2 levels, as well as IGF1R and STAT3 phosphorylation (pIGF1R, pSTAT3) in tissue biopsies, and H-score was defined for tumor cells, infiltrating immune cells, and fibroblasts in the TME. Membrane completeness (mc) parameter was included in pIGF1R scoring.
Results. NT219 Cmax and AUC demonstrated a dose dependent increase, with 50mg/kg dose mean human AUC reaching Human Equivalent Dose efficacy of animal models. Indeed, at this dose, anti-tumor activity in humans was also demonstrated with 2 confirmed partial responses (PR) reported. At the 50 mg/kg NT219 dose, out of 4 SCCHN pts, for whom pre-treatment biopsies were available, 3 were HPV negative and 2 of them achieved PR. Pretreatment biopsies of these 2 pts demonstrated high activated IGF1R membranal staining (Avg. mcH-score: 285, p-value:) and high activated STAT3 nuclear staining (Avg. H-score: 285), in contrast to the non-responding SCCHN pts (30 and 33, with p-value 0.017, 0.004 respectively). Inhibition of intratumoral IGF1R/IRS and STAT3 was demonstrated in on-treatment biopsies. Analysis will be presented at the conference.
Conclusion. NT219 in combination with cetuximab demonstrated safety and early activity with 2 confirmed PRs at 50mg/kg dose level in R/M SCCHN pts. This dose level was the first dose at which the observed NT219 exposure was within the range of the efficacious dose levels in pre-clinical models. Detection of activated IGF1R and STAT3 in responding pts, compared to the non-responding pts, suggests a potential use of these targets as biomarkers for future patient selection. This notion is further substantiated by the demonstration of NT219 on-target effects in on-treatment tumor biopsies. Upregulation of NT219 targets, IGF1R and STAT3, in HPV-negative SCCHN pts and their response to the NT219+cetuximab treatment, support further evaluation of this patient population.
Citation Format: Ari J. Rosenberg, Shumei Kato, Daniel Johnson, Aron Popovtzer, Vi K. Chiu, Ravit Geva, Hava Ben-David, Tomer Meirson, Michael Schickler, Hadas Reuveni. Early activity and biomarker evaluation of NT219 in combination with cetuximab in a Phase 1/2 study of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) [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 5181.