A randomized phase II trial published in Nature Medicine explored whether combining immune-modulating stereotactic body radiation therapy (iSBRT) with immune checkpoint inhibition could improve treatment responses in high-risk early estrogen receptor-positive (ER+)/HER2-negative breast cancer.
The Neo-CheckRay trial investigated whether radiotherapy could reshape the tumor microenvironment and make traditionally less immune-responsive breast cancers more sensitive to immunotherapy.
Addressing an Unmet Need in Luminal Breast Cancer
ER+/HER2− breast cancer represents the most common breast cancer subtype, but high-risk luminal B-like tumors continue to present therapeutic challenges. These tumors often have lower immune activity, reduced tumor-infiltrating lymphocytes, and lower PD-L1 expression, which may limit the effectiveness of immune checkpoint inhibitors.
Current management typically includes neoadjuvant chemotherapy, surgery, radiotherapy when indicated, and endocrine-based approaches, with additional targeted strategies for selected patients. However, recurrence risk remains significant in high-risk disease, highlighting the need for new treatment approaches.
Researchers hypothesized that stereotactic body radiation therapy could modify the tumor environment by increasing immune activation and improving recognition of cancer cells by the immune system.
The Neo-CheckRay Trial Design
The multicenter randomized phase II Neo-CheckRay trial enrolled 147 women with high-risk ER+/HER2− early breast cancer. Patients received neoadjuvant chemotherapy combined with immune-modulating SBRT, with treatment arms including:
- iSBRT alone without immune checkpoint inhibition
- iSBRT combined with the anti-PD-L1 antibody durvalumab
- iSBRT combined with durvalumab and the anti-CD73 antibody oleclumab
The radiotherapy approach consisted of 24 Gy delivered in three fractions to the primary breast tumor while aiming to preserve immune activity within tumor-draining lymph nodes.
Combining Radiation and Immunotherapy to Activate the Tumor Microenvironment
Unlike triple-negative breast cancer, where immunotherapy has already demonstrated clinical benefit in selected patients, ER+/HER2− tumors are generally considered more immune-resistant. The study explored whether radiation could help overcome this limitation.
Radiotherapy may stimulate immune responses by increasing tumor antigen release and promoting immune recognition. However, radiation can also activate immune-suppressive pathways, including the CD73-adenosine pathway, which became the rationale for investigating oleclumab in combination with durvalumab.
Improved Pathologic Responses With Immunotherapy Combination
In the intention-to-treat population, the primary endpoint of residual cancer burden (RCB) 0/1 was:
- 35.4% with iSBRT alone
- 45.1% with iSBRT plus durvalumab
- 47.9% with iSBRT plus durvalumab and oleclumab
Although numerical improvements were observed, the difference in the primary endpoint was not statistically significant.
Pathologic complete response (pCR) rates showed a similar trend:
- 16.7% with iSBRT alone
- 29.4% with durvalumab
- 33.3% with durvalumab plus oleclumab
In the predefined per-protocol population of MammaPrint High Risk patients, the double immunotherapy combination significantly improved pCR rates compared with iSBRT alone, reaching 35.6% versus 16.3%.
Particularly Promising Results in PD-L1-Negative Tumors
One of the most notable findings came from patients with PD-L1-negative tumors, a group traditionally considered less responsive to immune checkpoint blockade.
Among these patients, pCR rates increased from 3.4% with iSBRT alone to 28.1% with durvalumab and 30.0% with durvalumab plus oleclumab.
The findings suggest that immune-modulating radiation may help transform “immune-cold” tumors into a more immune-active state, potentially expanding the benefit of immunotherapy to patients who currently have limited options.
Biomarker Findings Support Immune Activation
Analysis of tumor samples showed that iSBRT was associated with changes in the tumor microenvironment, including increased immune-related activity after treatment. Paired biopsies collected before and after radiation demonstrated movement toward a more inflamed tumor phenotype in the immunotherapy-containing arms.
These biological findings support the concept that radiation may serve not only as a local treatment but also as an immune-modulating strategy.
What Comes Next for Immuno-Radiotherapy in Breast Cancer?
The Neo-CheckRay trial provides important evidence that combining radiation with immunotherapy may improve responses in selected high-risk ER+/HER2− breast cancers, particularly among patients with PD-L1-negative disease.
However, the study was a phase II trial, and larger studies are needed to determine whether this approach can improve long-term outcomes and become part of routine clinical practice.
The results add to a growing field exploring how radiation and immunotherapy can work together to overcome resistance mechanisms and personalize treatment for patients with difficult-to-treat breast cancer subtypes.
Title: Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2− breast cancer: a randomized phase 2 trial
Journal: Nature Medicine
Authors: Alex De Caluwé, Isabelle Desmoulins, Kim Cao, Vincent Remouchamps, Adinda Baten, Eleonore Longton, Karine Peignaux, Andrea Joaquin Garcia, David Venet, Luca Arecco, Elisa Agostinetto, Guilherme Nader-Marta, Zoë Denis, Jennifer Dhont, Paulus Kristanto, Xavier Catteau, Denis Larsimont, Roberto Salgado, Philip Poortmans, John Stagg, Christos Sotiriou, Martine Piccart, Michail Ignatiadis, Emanuela Romano, Laurence Buisseret.
Discover more articles like this on OncoDaily