Abstract A071: Immune biomarkers of response in a phase 1 trial of combined MEK/STAT3/PD-1 inhibition in metastatic pancreatic ductal adenocarcinoma (PDAC)

Abstract Background: PDAC remains resistant to immune checkpoint inhibition (ICI), in part due to a suppressive tumor microenvironment (TME) driven by oncogenic RAS and stromal interactions. Our preclinical data demonstrate that combined MEK and JAK/STAT3 inhibition reprograms the TME, reduces immunosuppressive myeloid cell populations, and restores effector T cell function, facilitating ICI sensitivity. Based on these findings, we conducted a phase 1 trial (NCT05440942) to evaluate the safety, preliminary efficacy, and immune biomarkers of trametinib (MEKi), ruxolitinib (JAK/STAT3i), and retifanlimab (anti–PD-1) (TRRf), in patients with metastatic PDAC as second or third-line therapy. Methods: The trial consisted of a dose escalation phase (Part 1, N=8) and an expansion phase (Part 2, N=20) at the target dose level (trametinib 2 mg PO daily, ruxolitinib 15 mg PO BID, retifanlimab 500 mg IV every 28 days). Peripheral blood and core biopsies were collected at baseline and after Cycle 1 of treatment cycle for biomarker analyses, including high-dimensional flow cytometry, cytokine profiling, and CODEX spatial immune profiling. Results: No dose-limiting toxicities were observed across all dose levels. The most common grade 3/4 adverse events (AE’s) were fatigue (32%), anemia (29%) and transaminase increase (18%). Among 20 patients in part 2, 2 achieved partial responses and 5 had stable disease for over 16 weeks (objective response rate 10%; disease control rate 35%). In-depth immune profiling of 5 responders (defined as having disease control) and 5 non-responders after Cycle 1 revealed that responders exhibited expansion of CD4+ early effector and memory T cells with increased levels of Granzyme B and CD107a, consistent with enhanced cytotoxic potential. Responders also demonstrated a reduction in monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory B cells, along with increases in mature NK cells. In contrast, non-responders showed expansion of total CD19+ B cells along with their CD20+ subset of memory B cells and downregulation of CD38 on CD4+ T cells, suggestive of impaired activation. Notably, plasma IL-12p70 and IFN-γ levels were significantly elevated after one treatment cycle in all six patients tested, regardless of response status, supporting TRRf-induced systemic Th1 immune polarization. Conclusions: TRRf therapy was well tolerated in patients with metastatic PDAC and induced a distinct immune reprogramming in responders characterized by activation of memory/effector CD4+ T cells, innate cytotoxicity via NK cell expansion, and systemic Th1 cytokine induction. These circulating immune phenotypes and cytokine profiles may serve as predictive biomarkers and provide mechanistic insight into response to MEK/STAT3-targeted immunotherapy in PDAC. Citation Format: Peter Joel. Hosein, Sayan Chakraborty, Anna Bianchi, Yolanda Justal, Nkiruka Ezenwajiaku, Maria Vanessa. Yow, Chloe Brown, Melinda Boone, Edmond Box, Juan Pablo. Vaccario, Paolo Serafini, Jashodeep Datta, Nipun Merchant. Immune biomarkers of response in a phase 1 trial of combined MEK/STAT3/PD-1 inhibition in metastatic pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A071.