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

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 (No_ICI), 45.1% in the Single_ICI arm, and 47.9% in the Double_ICI 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 No_ICI and 35.6% in Double_ICI (p=0.040). Among PD-L1-negative patients (n=91), pCR rates were 3.4% (No_ICI), 28.1% (Single_ICI), and 30.3% (Double_ICI). 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.