Nature Medicine
2026-06-25
DOI: HASH:6a8e25e74ede15f0136137a0830810ef
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 . In the randomized phase 2 Neo-CheckRay trial, patients with early-stage ER+HER2− breast cancer received neoadjuvant immune-modulating stereotactic body radiation therapy with or without durvalumab, and with or without the anti-CD73 antibody oleclumab, leading to encouraging clinical responses when durvalumab was added including in patients with PD-L1-negative tumors.