Randomized phase 2 trial of neoadjuvant SBRT with durvalumab and oleclumab in ER-positive, HER2-negative breast cancer

Patients with ER-positive, HER2-negative early breast cancer (ER+ HER2- EBC) have low pathologic complete response (pCR) rates after neoadjuvant chemotherapy. Immune checkpoint inhibitors (ICIs) provide limited benefit in PD-L1-negative tumors, characterized by an immune-cold tumor microenvironment. The phase 2 Neo-CheckRay trial, at seven sites in Belgium and France, investigated the hypothesis that immune-modulating stereotactic body radiation therapy (iSBRT; 3 x 8 Gy) could enhance response through tumor microenvironment reprogramming, and that CD73 blockade could further improve efficacy. A total of 147 female patients with high-risk ER+ HER2- EBC received iSBRT alone (no-ICI group; n=48), iSBRT plus anti-PD-L1 durvalumab (single-ICI group; n=51), or iSBRT plus durvalumab and anti-CD73 oleclumab (double-ICI group; n=48). The primary endpoint, residual cancer burden 0/1 rate, was 35.4% in the no-ICI group, 45.1% in the single-ICI group, and 47.9% in the double-ICI group, without statistically significant differences, while 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% (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.The authors conclude that these findings suggest that iSBRT plus anti-PD-L1 may convert immune-cold ER+ HER2- EBC to more inflamed tumors and improve response, particularly in PD-L1 negative disease.