Abstract CT065: Modakafusp alfa shows intratumoral immune pharmacodynamics (PD) in a subset of patients (pts) in a phase 1b study in advanced/metastatic solid tumors

Abstract

Abstract Background: Modakafusp alfa (moda), a novel immunocytokine, is an innate immune enhancer comprising an anti-CD38 IgG4 antibody fused to 2 attenuated interferon (IFN) α2b molecules. Moda is being evaluated in phase 1/2 trials for multiple myeloma and in a phase 1/2 trial in solid tumors. Here, we present PD data in tumor biopsies and peripheral blood (PB) from the phase 1/2 study of moda as monotherapy in pts with advanced/metastatic solid tumors (NCT04157517). Methods: A total of 21 pts were treated with moda 0.1-1.5 mg/kg every 3 weeks. Tumor biopsy samples were collected at screening and on cycle 2, day 2 (C2D2). Biopsies were evaluated by multiplex immunofluorescence (using a Multiomyx platform) and RNASeq. PB samples were collected pre-dose on C1D1 and at timepoints after treatment. PB samples were evaluated by CyTOF to assess PD changes in immune cells. Results: No clinical tumor responses (partial or better) were observed in the 21 pts. Analysis of tumor biopsies revealed two subgroups defined by differences in upregulation of CD38 expression after moda treatment, with differential intratumoral PD changes. The CD38 gene has IFN response elements within its promoter region. Thus, correlation of tumor PD with changes in CD38 expression is of interest because, along with being a target of moda, an increase in CD38 expression may indicate drug activity in the tumor microenvironment. Interestingly, in the subset of pts in whom an increase in the percentage of CD38+ lymphocytes in response to moda was reported, there were also increases in CD8 and CD4 T cell activation, (%CD69) as well as CD8 T cell cytotoxic function (%GzB). Additionally, moda led to increase in CD14+CD16+ intermediate monocytes, indicating an enhanced myeloid response in several pts, and minimal changes in FoxP3+ Tregs regardless of changes in CD38 expression. Moda treatment led to an increase in activated and cytolytic natural killer (NK) and CD8 T cells in all pts. This was accompanied by increased NK and CD8 T cell proliferation (%Ki67) in PB, without sustained increase in exhaustion markers. CD4 T cells were also activated in response to moda and there was no increase in circulating FoxP3+ Tregs. Enhanced myeloid cell response, measured by increased proliferation of monocytes and dendritic cells, along with upregulation of costimulatory molecules, were also seen. Importantly, immune PD changes in the PB were seen in most pts and there were no immune PD differences identified between the two patient subsets defined in the biopsy analysis. Conclusion: PD biomarker data from this phase 1/2 trial in pts with advanced solid tumors demonstrated that moda enhances innate and adaptive immune activation in PB and within tumors. The presence of a differential intratumoral PD response in a subset of pts with elevated CD38+ cells highlights that tumor intrinsic factors may play a role in driving moda’s activity in tumors. Citation Format: Gurpanna Saggu, Janet L. Markman, Min Young Lee, Faith Dunbar, Adarsh Joshi, Shining Wang, Sabrina Collins. Modakafusp alfa shows intratumoral immune pharmacodynamics (PD) in a subset of patients (pts) in a phase 1b study in advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT065.