Abstract A129: Phasic Hedgehog Inhibition Primes the Pancreatic Tumor Microenvironment to Enhance Chemoimmunotherapy in Metastatic Pancreatic Ductal Adenocarcinoma: Results from the Phase 1b/2 NUMANTIA Trial
TL;DR
CAF-directed stromal priming as a strategy to enhance chemoimmunotherapy and warrant evaluation in randomized studies with integrated biomarker analyses are supported.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to immunotherapy because of its dense, immunosuppressive tumor microenvironment (TME). Preclinical studies demonstrated that Hedgehog (Hh) pathway inhibition remodels cancer-associated fibroblasts (CAFs), creating a therapeutic window in which immune checkpoint blockade becomes effective. We evaluated this stromal priming strategy in the Phase 1b/2 NUMANTIA trial. Twenty-eight patients with previously untreated metastatic PDAC received gemcitabine/nab-paclitaxel (GnP) together with intermittent oral Smoothened inhibitor NLM-001 and the anti-CTLA-4 antibody zalifrelimab. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), circulating tumor DNA (ctDNA), and translational analyses of paired tumor biopsies using multiplex immunofluorescence and spatial transcriptomics. The combination was well tolerated, with no treatment discontinuations attributable to toxicity. Grade 3-4 adverse events were consistent with chemotherapy and included neutropenia (46.4%), asthenia (21.4%), and neurotoxicity (14.3%). ORR was 50.0% (95% CI, 29.1-70.9%) with a disease control rate of 95.5%. Median PFS was 7.3 months and median OS was 11.5 months. Patients achieving ctDNA clearance by cycle 4 experienced significantly longer PFS (10.7 vs. 6.0 months; p<0.0001) and a trend toward improved OS. Paired biopsy analyses demonstrated remodeling of the TME following Hh priming, including increased CD4+ and CD8+ T-cell infiltration, reduced regulatory T cells, decreased αSMA/FAP CAF ratio, collagen remodeling, and enrichment of tertiary lymphoid structure-associated gene signatures. Spatial transcriptomic analyses further demonstrated reduced tumor cell abundance with increased immune infiltration and CAF polarization, supporting successful stromal reprogramming toward an immune-permissive microenvironment. Mechanistically informed, intermittent Hh inhibition combined with GnP and CTLA-4 blockade demonstrated encouraging clinical activity together with evidence of stromal and immune remodeling in metastatic PDAC. These findings support CAF-directed stromal priming as a strategy to enhance chemoimmunotherapy and warrant evaluation in randomized studies with integrated biomarker analyses. AI-assisted language editing was used in the preparation of this abstract, with all scientific content reviewed and verified by the authors. Valerie S. Kalluri, Bruno Bockorny, Evelio Perea Borobio, Teresa Macarulla, Roberto Pazo Cid, Laura Medina, Aitziber Gil-Negrete, Fernando Rivera, Vanesa Varela, Alejandro Martin-Munoz, Yanira Ruiz-Heredia, Bingrui Li, Patience Kelly, Barbara Moreno Diaz, Shreyasee V. Kumbar, Hikaru Sugimoto, Raghu Kalluri, Manuel Hidalgo. Phasic Hedgehog Inhibition Primes the Pancreatic Tumor Microenvironment to Enhance Chemoimmunotherapy in Metastatic Pancreatic Ductal Adenocarcinoma: Results from the Phase 1b/2 NUMANTIA Trial [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A129.
