Journal Article Ahead of print 4 citations
PubMed: 42350643 DOI: 10.1038/s41591-026-04453-z
Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER +HER2 - breast cancer: a randomized phase 2 trial.
Nat Med
Authors: Alex De Caluwé, Isabelle Desmoulins, Kim Cao, Vincent Remouchamps, Adinda Baten, Eleonore Longton, Karine Peignaux, Andrea Joaquin Garcia, David Venet, Luca Arecco, Elisa Agostinetto, Guilherme Nader-Marta, Zoë Denis, Jennifer Dhont, Paulus Kristanto, Xavier Catteau, Denis Larsimont, Roberto Salgado, Philip Poortmans, John Stagg, Christos Sotiriou, Martine Piccart, Michail Ignatiadis, Emanuela Romano, Laurence Buisseret
Affiliations
- Institut Jules Bordet, Hôpitaux Universitaires de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium.
- Centre Georges-François Leclerc, Université Bourgogne Europe, Dijon, France.
- Institut Curie, Paris, France.
- CHU St Elisabeth, Namur, Belgium.
- Universitaire Ziekenhuizen Leuven, Leuven, Belgium.
- Hôpital Universitaire St Luc, Brussels, Belgium.
- Institut Jules Bordet, Hôpitaux Universitaires de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium.
- ZAS Hospitals, Antwerp, Belgium.
- Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia.
- Iridium Netwerk, Antwerp, Belgium.
- University of Antwerp, Antwerp, Belgium.
- Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
Abstract
Patients with estrogen receptor-positive (ER +), HER2-negative, early breast cancer (BC) have low pathologic complete response (pCR) rates following neoadjuvant chemotherapy. Immune checkpoint inhibitors (ICIs) provide limited benefit in programmed death-ligand 1 (PD-L1)-negative tumors, characterized by an immune-cold tumor microenvironment. Here we hypothesized that immune-modulating stereotactic body radiation therapy (iSBRT; 3 × 8 Gy) could enhance response through tumor microenvironment reprogramming, and that CD73 blockade could further improve efficacy. We conducted a phase 2, randomized, multicenter trial (Neo-CheckRay) in 147 female patients with high-risk, ER +HER2 - early BC. Patients received neoadjuvant chemotherapy plus iSBRT alone (No_ICI), with anti-PD-L1 durvalumab (Single_ICI) or with durvalumab plus anti-CD73 oleclumab (Double_ICI). In the intention-to-treat population, the primary endpoint, residual cancer burden 0/1 rate, was 35.4% with No_ICI, 45.1% with Single_ICI and 47.9% with Double_ICI, without statistically significant differences. pCR rates were 16.7%, 29.4% and 33.3%, respectively (P = 0.059). In the per-protocol population (MammaPrint High Risk, n = 131), pCR rates were 16.3%, 32.6% and 35.6%, respectively (P = 0.040). Among PD-L1-negative tumors (n = 91), pCR rates were 3.4%, 28.1% and 30.0%, respectively. No new safety signals were observed. Baseline transcriptomic analysis showed low immune signature expression in PD-L1-negative tumors. Paired baseline and on-treatment biopsies obtained 1 week after iSBRT demonstrated tumor microenvironment reprogramming toward an inflamed phenotype in the iSBRT + anti-PD-L1 arms. These findings suggest that iSBRT + anti-PD-L1 may convert immune-cold ER +HER2 - BC into more inflamed tumors and improve response, particularly in PD-L1-negative disease. ClinicalTrials.gov registration: NCT03875573 .
MeSH
Radiotherapy, Breast Neoplasms, Molecular Biology, Cold Temperature, Neoplasms, Drug Therapy, Breast, Therapeutics, Tumor Microenvironment, Chemotherapy