Immunotherapy Plus iSBRT Boosts Response in PD-L1-Negative Breast Cancer

The phase 2 Neo-CheckRay (NCT03875573) randomized trial has found that pairing immune-modulating stereotactic body radiation therapy (iSBRT) with neoadjuvant chemotherapy and the anti-PD-L1 antibody durvalumab (Imfinzi) meaningfully improved pathologic response in patients with high-risk, estrogen receptor-positive (ER+), HER2-negative early breast cancer, with the largest gains occurring in tumors that lacked PD-L1 expression.

Results of the Neo-CheckRay trial, published in Nature Medicine, also examined whether adding the anti-CD73 antibody oleclumab could further amplify the immune-modulating effects of radiation, although this triplet combination did not outperform durvalumab alone.

What did the Neo-CheckRay trial evaluate?

Neo-CheckRay was a prospective, randomized, open-label, multicenter phase 2 trial conducted at 7 sites in Belgium and France. Investigators enrolled 147 patients with high-risk ER+/HER2− early breast cancer identified by the MammaPrint High Risk genomic signature and randomly assigned them 1:1:1 to receive neoadjuvant chemotherapy plus iSBRT alone (no immune checkpoint inhibitor [ICI] arm; n = 48), iSBRT plus durvalumab (single ICI arm; n = 51), or iSBRT plus durvalumab and oleclumab (double ICI arm; n = 48).

Chemotherapy consisted of weekly paclitaxel followed by dose-dense doxorubicin-cyclophosphamide, and iSBRT was delivered as three 8-Gy fractions targeting only the primary tumor while sparing the axilla and nodal regions. The trial's primary end point was residual cancer burden (RCB) 0/1 at surgery, with pathologic complete response (pCR) as a key secondary end point. Patients were stratified by baseline PD-L1 status, nodal status, and tumor stage.

How did response rates compare across the three arms?

In the intention-to-treat (ITT) population, RCB 0/1 rates were 35.4% (95% CI, 21.9%-48.9%) with no ICI, 45.1% (95% CI, 31.4%-58.8%) with single ICI, and 47.9% (95% CI, 33.8%-62.0%) with double ICI, a difference that did not reach statistical significance. The pCR rates followed a similar pattern: 16.7% (95% CI, 6.1%-27.2%), 29.4% (95% CI, 20.0%-46.7%), and 33.3% (95% CI, 21.6%-49.5%), respectively (P = .059). In the predefined per-protocol population of confirmed MammaPrint patients who were high risk (n = 131), the pCR benefit reached significance, rising from 16.3% (95% CI, 5.2%-27.3%) with no ICI to 32.6% (95% CI, 18.6%-46.6%) with single ICI and 35.6% (95% CI, 21.6%-49.5%) with double ICI (P = .04).

Why did PD-L1-negative tumors see the greatest benefit?

The most notable finding emerged in the prespecified PD-L1-negative subgroup, which made up 61.9% of the ITT population. Among these immunologically “cold” tumors, pCR rates rose sharply with the addition of immunotherapy, from just 3.4% with iSBRT and chemotherapy alone to 28.1% with single ICI and 30.0% with double ICI. The absolute pCR increase with immunotherapy in PD-L1-negative disease was 30.3%, suggesting that radiation-driven remodeling of the tumor microenvironment may help sensitize otherwise immune-cold tumors to checkpoint blockade. Patients who were node-positive, PD-L1-negative derived particular benefit.

An exploratory analysis also found that the immunotherapy benefit disappeared when incidental radiation dose to the axilla exceeded 1 Gy, while limiting axillary dose below that threshold was associated with a 27.1% increase in pCR when durvalumab was added.

Did adding anti-CD73 oleclumab provide additional benefit?

Despite preclinical rationale that CD73 blockade could counter radiation-induced adenosine-mediated immunosuppression, the double ICI combination of oleclumab plus durvalumab did not significantly improve pCR or RCB 0/1 rates over durvalumab alone. Investigators noted that faster tumor clearance in the oleclumab arm may have reduced the number of paired on-treatment biopsies available for transcriptomic analysis, limiting the ability to fully characterize immune activation in this group.

What do the safety data show?

Grade 3 or higher treatment-related adverse effects (AEs) occurred in 29.2% of patients in the no ICI arm, compared with 64.7% in the single ICI arm and 70.8% in the double ICI arm, driven largely by hematologic toxicities such as neutropenia and anemia. Immune-mediated AEs of any grade were reported in 6.3% of patients without ICI vs 49.0% and 43.7% in the single ICI and double ICI arms, most commonly thyroid dysfunction. No treatment-related deaths occurred, iSBRT was not associated with any grade 3 or higher radiation toxicity, and rates of breast-conserving surgery were similar across arms.

What are the clinical implications for the care team?

Neo-CheckRay is a hypothesis-generating phase 2 study with a modest sample size and a median follow-up of 34 months; event-free survival data remain immature, with 3-year estimates of 90.6% in the no ICI arm, 100% in the single ICI arm, and 97.9% in the double ICI arm. The authors emphasized that longer follow-up and confirmatory phase 3 testing will be needed to determine whether the observed pathologic response benefit translates into improved long-term outcomes.

The data suggest that combining radiation with anti-PD-L1 therapy may offer a way to convert immunologically cold, PD-L1-negative ER+/HER2− tumors into more treatable, inflamed disease, an approach that could eventually reshape neoadjuvant strategies for a population that has historically derived little benefit from immunotherapy.

Reference

De Caluwé A, Desmoulins I, Cao K, et al. Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2− breast cancer: a randomized phase 2 trial. Nat Med. 2026;32:2461-2472. doi:10.1038/s41591-026-04453-z