August 4, 2025

Neoadjuvant immune-modulating SBRT and anti-CD73 to increase response to anti-PD-L1 and chemotherapy in early ER+/HER2- breast cancer: primary endpoint and translational results from the randomized Neo-CheckRay trial

Key Points

The core finding reveals improved pathological complete response rates in ER+/HER2- breast cancer with iSBRT and immune therapies.
Secondary endpoints indicate a significant increase in pCR rates among high-risk patients treated with dual immune checkpoint inhibitors.
The randomized trial involved 147 patients and assessed treatment efficacy using intention-to-treat analysis.
These results suggest a new approach for treating immune-cold breast cancer tumours using targeted therapies and radiation.

Abstract

Abstract Patients with oestrogen receptor-positive (ER+), HER2-negative, early breast cancer (BC) have low pathological complete response (pCR) rates following neoadjuvant chemotherapy (NACT). Phase 3 trials showed that adding an anti-PD-1 immune checkpoint inhibitor (ICI) improves pCR, but there was less benefit in the PD-L1 negative tumours, characterised by an immune “cold” tumour microenvironment (TME). We hypothesized that immune-modulating stereotactic body radiation therapy (iSBRT) could enhance treatment response by reprogramming the immune deprived TME in early ER+/HER2- BC. We further proposed that adding an anti-CD73 antibody could reduce adenosine-mediated immunosuppression and increase efficacy. We conducted a phase 2, randomized, multicentre trial (Neo-CheckRay) evaluating NACT plus iSBRT, with or without durvalumab (anti-PD-L1) and with or without oleclumab (anti-CD73) in 147 patients with high-risk, early, ER+/HER2- BC. In the intention-to-treat (ITT) population, primary endpoint Residual Cancer Burden (RCB) 0 or 1 was achieved in 35. 4% of patients receiving iSBRT + NACT alone (NoICI), 45. 1% in the SingleICI arm, and 47. 9% in the DoubleICI arm (p=0. 203). Secondary endpoint pCR rates were 16. 7%, 29. 4%, and 33. 3% (p=0. 059), respectively. In the predefined per-protocol population, which included only MammaPrint High-Risk patients (n=131), the secondary endpoint pCR was met: 16. 3% in NoICI and 35. 6% in DoubleICI (p=0. 040). Among PD-L1-negative patients (n=91), pCR rates were 3. 4% (NoICI), 28. 1% (SingleICI), and 30. 3% (DoubleICI). In contrast, no significant differences between treatment arms were observed in PD-L1-positive patients. Whole-transcriptome analysis revealed low expression of immune signatures at baseline in PD-L1-negative patients, while biopsies 1 week after iSBRT indicated TME reprogramming toward an inflamed phenotype with iSBRT + ICI. In conclusion, iSBRT combined with NACT and anti-PD-L1 significantly improves pCR in PD-L1-negative, ER+/HER2- BC, suggesting a novel strategy for immune-cold tumours. Clinical trials. gov identifier: NCT03875573.

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