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

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 (NoICI), with anti-PD-L1 durvalumab (SingleICI) or with durvalumab plus anti-CD73 oleclumab (DoubleICI). In the intention-to-treat population, the primary endpoint, residual cancer burden 0/1 rate, was 35. 4% with NoICI, 45. 1% with SingleICI and 47. 9% with DoubleICI, 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.