Abstract
Abstract Background Subasumstat (TAK-981, suba) is a first-in-class innate immunity enhancer that unlocks innate/adaptive immune responses to target tumors through SUMOylation inhibition, which may enhance antitumor activity by restoring endogenous type 1 IFN signaling in immune cells. In the phase 1/2 study (NCT03648372), suba showed dose-dependent upregulation of an IFN-1 gene signature in peripheral blood (PB) and plasma levels of several IFN-1-induced cytokines, and an increase in activated NK, CD8, and CD4 T cells in PB. Here, we report pharmacodynamic data from skin and tumor biopsy samples from this study. Methods In phase 1, 84 pts received suba IV at escalating doses (3-120 mg) twice-weekly (BIW) or once-weekly in 21-day cycles. In phase 2, 25 pts with refractory NSCLC, cervical cancer, or CRC received suba 90 mg BIW. Skin and tumor biopsies were collected at screening and on cycle 1, day 8 (C1D8, skin) or C2D8 (+7 days; tumor). Target engagement (TE) and levels of SUMO2/3-conjugates were assessed using IHC. Immune activation in the tumor microenvironment (TME) was measured by IHC and multiplex IF. Results In skin samples collected 1-3 hours after D8 dosing, suba ≥10 mg demonstrated dose-dependent TE as seen by suba-SUMO adduct formation and dose-dependent SUMO2/3 inhibition at ≥60 mg. Assays of paired tumor samples from pts with CPI-naïve MSS-CRC (90 mg BIW, n=3), cervical cancer (90 mg BIW, n=1), CPI-exposed non-squamous NSCLC (90 mg BIW, n=2), and melanoma (25 mg BIW, n=1) showed robust TE in the post-dose sample, along with SUMO2/3 inhibition or stabilization. Suba’s effects on the TME were assessed through PD-L1 IHC. There was an increase in PD-L1 combined positive score in most on-treatment tumors, consistent with suba’s ability to enhance IFN production, leading to induction of an inflammatory landscape in the TME. Multiplex IF analysis revealed significant CD8+ and CD4+ T cell infiltration in samples from CPI-naïve (cervical cancer) and CPI-exposed (melanoma and NSCLC) pts. In contrast, biopsies obtained from MSS-CRC pts did not exhibit an increase in T cell density, suggesting that “cold” tumors may be less susceptible to suba-mediated immune remodeling. Accordingly, biopsies from pts with cervical cancer and melanoma displayed a significant increase in T cell activation and density of activated CD11c+HLA-DR+ myeloid dendritic cells within the TME, as well as a marked increase in HLA-class I expression. Conclusion Suba-mediated inhibition of SUMOylation led to marked changes in the TME across different indications, supporting the hypothesized immune-activating mechanism of action of the drug. Our findings support continued development of suba in solid tumors. Suba is being evaluated in combination with pembrolizumab in NSCLC, cervical cancer, and melanoma (NCT04381650). Citation Format: Dina Stroopinsky, Slawomir Mandzuik, Daniel Anderson, José-Ángel Hernández-Rivas, Hadeel Assad, Allison Berger, Aleksander Chudnovsky, Qi Dong, Afshin Dowlati, Dejan Juric, Razelle Kurzrock, Iwona Lugowska, Kelly Richter, Jordi Rodón, David Schröder, Siddha Kasar, Anthony Olzanski. Pharmacodynamic analysis from a phase 1/2 study of subasumstat (TAK-981) as single agent in patients (pts) with advanced/refractory 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 CT061.
Published Version
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