Abstract 1801: Development of a comprehensive biomarker strategy to support phase 1 clinical trial of SRK-181 the latent TGFβ1 inhibitor

Abstract

TGFβ signaling appears to be a key mediator of primary resistance to programmed cell death protein (PD-1) pathway blockade. SRK-181 is an investigational stage, high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. Preclinical data demonstrate that combining SRK-181 with a PD-1 inhibitor modulates tumor microenvironment (TME), including an influx of CD8 positive T cells that correlates with anti-tumor responses. The ongoing DRAGON trial is a multi-center, open-label, Phase 1, first in-human (FIH), dose-escalation, and dose-expansion study. The goal of the trial is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SRK-181 administered alone and in combination with an anti-PD-(L)-1 in adult patients with locally advanced or metastatic solid tumors. To support this ongoing DRAGON clinical trial and further explore the mechanism of action of SRK-181, a comprehensive biomarker strategy is being developed to assess the alternation of immune profile in TME and potential predictors of therapeutic response to SRK-181. Here we describe the development and refinement of several biomarker assays. First, an image analysis-based algorithm for CD8 immunohistochemistry (IHC) is established utilizing human cancer tissue in a pre-clinical study. This novel digital pathology analysis enables identification of CD8 positive T cells in discrete compartments, including the tumor nests, stroma and tumor/stromal margins, to better capture the heterogeneity of the CD8 signal within tissues. Second, we describe methods to evaluate the TGFβ pathway including quantitative analysis of tumor tissue phospho-Smad2 and circulatory levels of TGFβ1 ligand. A companion assay to exclude blood samples with nonspecific background signals has been characterized and will be performed in parallel when evaluating circulatory TGFβ1 in clinic. In summary, we present several novel, tailored biomarker readouts that are part of a broader biomarker strategy aimed at maximizing detection of relevant clinical data to both support the ongoing clinical trial and provide further insight into the mechanism of action of SRK-181. Citation Format: Christopher Brueckner, Ryan Faucette, Charles Caldwell, Jr., Sofia Reitsma, Stefan Wawersik, Ashish Kalra, Lu Gan, Si Tuen Lee-Hoeflich. Development of a comprehensive biomarker strategy to support phase 1 clinical trial of SRK-181 the latent TGFβ1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1801.