Abstract LB397: Biomarker-guided dose selection in the iintune-1 study of dazostinag,a STING agonist, alone and in combination with pembrolizumab for patients with metastatic solid tumors

Abstract Background: The dazostinag (TAK-676) STING agonist activates innate and adaptive immune responses, including dose-dependent induction of cytokine responses and activation/proliferation of immune cells in preclinical tumor models. We present biomarker and pharmacokinetic (PK) data from the dose escalation portion of iintune-1 (NCT04420884), a phase 1 study of dazostinag as a single agent (SA) or in combination with pembrolizumab (pembro) in advanced or metastatic solid tumors. Biomarker data in conjunction with PK, safety, and efficacy was evaluated to inform dazostinag dose selection for dose expansion and optimization cohorts. Methods: Patients (pts) with advanced or metastatic solid tumors were enrolled into escalating dose cohorts from 0.1 to 14 mg dazostinag (weekly, IV) SA or in combination with pembro, (200 mg, every 3 weeks, IV). Peripheral blood biomarker samples were collected on days 1, 4, 8, and 15 of cycle 1 (pre-dose, 6, 10 and 24 hrs post-dose) and day 1 of cycle 2 (pre-dose, 6 hrs post-dose). Blood biomarker assessments included circulating cytokines/chemokines, PBMC RNA-sequencing, and flow cytometry immunophenotyping. In a subset of pts where baseline and paired on-treatment tumor biopsies were available, immunohistochemistry (PD-L1+ and CD8+) was performed to assess the impact of treatment on T-cell infiltration and modulation of tumor microenvironment. ctDNA assessments were done in a subset of pts (responders, n=3; non-responders, n=17) to determine association with anti-tumor activity per RECIST v1.1. Results: A total of 126 pts were treated during dose escalation: 50 pts received dazostinag as a SA and 76 received it in combination with pembro. Dose exposure was similar between the SA and combination cohorts with a terminal half-life of 1.4 ± 0.75 hours at doses up to 14 mg. No PK accumulation was observed between cycles. Induction of STING gene signature (Ding et al, AACR 2025, #6689) and IFN-γ was dose responsive, with the timing of maximum fold expression shifting from 10 hrs to 6hrs with higher dazostinag doses. Dazostinag in combination with pembro demonstrated a greater induction of the STING gene signature. Specifically, 14 mg dazostinag induced a median fold-increase of 49X in IFN-γ expression compared with 27X observed for 5 mg. Tumor biopsies indicated enhanced T-cell infiltration at dazostinag ≥5 mg. Furthermore, molecular responses assessed through ctDNA were enriched in pts who achieved a clinical response compared to non-responders. Conclusions: Dazostinag combined with pembro enhanced peripheral anti-tumor immune cell activity, CD8 T-cell tumor infiltration, and radiographic responses. Based on the totality of safety, clinical, PK and pharmacodynamics data, 5 mg and 14 mg dazostinag combined with pembro were selected for dose expansion and optimization in head & neck and colorectal tumors. Citation Format: Radha Ramesh, Kai Ding, Xin Tong, Ruichao Xu, Samanthi Perera, Vicky Appleman, Yury Sheykin, Cong Li, Jason J. Luke, Xin Gao, Anthony J. Olszanski, Rachel E. Sanborn, Gerald S. Falchook, Sandip P. Patel, Philippe L. Bedard, Douglas W. Orr, Patricia LoRusso, Harry Huang, Jeffrey Raizer, John Gibbs, Neil Lineberry, Richard C. Gregory. Biomarker-guided dose selection in the iintune-1 study of dazostinag,a STING agonist, alone and in combination with pembrolizumab for patients with metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB397.