A phase Ib/II trial of XL888 (HSP90 inhibitor) and pembrolizumab in metastatic pancreatic cancer with translational immune profiling

Pancreatic adenocarcinoma is marked by high mortality and limited treatment options. In mice, HSP90 inhibition limits cancer-associated fibroblasts activation and enhances T cell infiltration, sensitizing tumors to PD-1 blockade. We hypothesized that co-administration of pembrolizumab (anti-PD-1) with XL888 (an HSP90 inhibitor) would be safe and induce measurable immunological changes in the PDAC tumor microenvironment that could influence clinical outcome. We report results from an expansion cohort of patients with advanced PDAC (n = 16), who were enrolled in a single-center, open-label, nonrandomized, dose-escalation study. Patients received one cycle of either pembrolizumab (200 mg) alone or in combination with XL888 (90 mg, orally twice per week) over a 21-day cycle, followed by crossover to combination therapy. Peripheral blood and image guided liver biopsies were collected on Day 1 before treatment (C1D1) and Day 15 on-treatment (C1D15) for correlative studies. The combination regimen was well-tolerated with no unexpected adverse events. No objective responses were observed; two patients (13.3 %) achieved stable disease, while the remaining 13 (86.7 %) experienced disease progression. Median progression-free survival was 2.0 months, and median overall survival was 4.4 months. Treatment was associated with increased circulating Th1-associated cytokines and chemokines. Peripheral blood mononuclear cell (PBMC) analysis revealed elevated terminal effector CD8⁺ T cells and CD4⁺ regulatory T cells in the combination arm compared to pembrolizumab alone. Paired liver biopsies revealed no significant changes across treatment groups. While the combination of XL888 and pembrolizumab was safe and induced systemic immune modulation, limited clinical efficacy was observed and did not impact the PDAC TME.