Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2- breast cancer: a randomized phase 2 trial

De Caluw&#233;, A; Desmoulins, I; Cao, K; Remouchamps, V; Baten, A; Longton, E; Peignaux, K; Joaquin Garcia, A; Venet, D; Arecco, L; Agostinetto, E; Nader-Marta, G; Denis, Z; Dhont, J; Kristanto, P; Catteau, X; Larsimont, D; Salgado, R; Poortmans, P; Stagg, J; Sotiriou, C; Piccart, M; Ignatiadis, M; Romano, E; Buisseret, L

Author(s): De Caluwé, A; Desmoulins, I; Cao, K; Remouchamps, V; Baten, A; Longton, E; Peignaux, K; Joaquin Garcia, A; Venet, D; Arecco, L; Agostinetto, E; Nader-Marta, G; Denis, Z; Dhont, J; Kristanto, P; Catteau, X; Larsimont, D; Salgado, R; Poortmans, P; Stagg, J; Sotiriou, C; Piccart, M; Ignatiadis, M; Romano, E; Buisseret, L;
Details: Publication Year 2026-07,Volume 32,Issue #7,Page 2461-2472
Journal Title: Nature Medicine
Publication Type: Research article
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 .
Publisher: Springer Nature
Keywords: Humans; Female; Neoadjuvant Therapy; *Antibodies, Monoclonal/administration & dosage/therapeutic use/adverse effects; *Breast Neoplasms/pathology/genetics/radiotherapy/drug therapy/therapy/metabolism; Erb-b2 Receptor Tyrosine Kinases/metabolism/genetics; Middle Aged; Receptors, Estrogen/metabolism/genetics; *Radiosurgery/methods; Aged; Pathologic Complete Response; Adult; Tumor Microenvironment/drug effects
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41591-026-04453-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41591-026-04453-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-07-07 01:21:41

Last Modified: 2026-08-11 02:01:22