Neoadjuvant iSBRT Plus Durvalumab Boosts pCR in Cold Breast Tumors

Adding immune-modulating stereotactic body radiation therapy (iSBRT) and anti–PD-L1 checkpoint blockade to neoadjuvant chemotherapy nearly doubled pathologic complete response (pCR) rates in patients with high-risk, estrogen receptor–positive (ER+), HER2-negative (–) early breast cancer, according to results of the phase 2 Neo-CheckRay trial (NCT03875573) published in Nature Medicine.¹ The benefit was most pronounced among patients with PD-L1–negative, immunologically "cold" tumors, a population that has historically derived little advantage from checkpoint inhibition.

In the intention-to-treat (ITT) population of 147 patients randomized 1:1:1, the primary end point—residual cancer burden (RCB) 0/1 at surgery—was achieved by 35.4% of patients who received iSBRT with chemotherapy alone (no ICI arm), 45.1% of those who added durvalumab (Imfinzi; single ICI arm), and 47.9% of those who added durvalumab plus the anti-CD73 antibody oleclumab (double ICI arm). These differences did not reach statistical significance (no ICI vs double ICI, P =.21). The secondary end point of pCR (ypT0/Tis, ypN0) followed a similar pattern: 16.7%, 29.4%, and 33.3%, respectively (P =.059 for no ICI vs double ICI). In the predefined per-protocol population of 131 patients with confirmed MammaPrint High Risk status, the pCR improvement with double ICI reached significance (16.3% vs 35.6%; P =.04).

The subgroup analysis drew particular attention from investigators. Among the 91 patients (61.9% of the ITT population) with PD-L1–negative tumors (immune cell score less than 1% by the VENTANA SP263 assay), pCR rates rose from 3.4% with iSBRT alone to 28.1% with durvalumab and 30.0% with durvalumab plus oleclumab. No such benefit was observed among PD-L1–positive tumors. This pattern contrasts with the phase 3 CheckMate 7FL (NCT04109066) and KEYNOTE-756 (NCT03725059) trials, in which anti–PD-(L)1 added to standard neoadjuvant chemotherapy without radiation produced its greatest benefit in PD-L1–positive disease and only modest pCR increases of 3.5% and 4.5%, respectively, in PD-L1–negative subgroups.²,³

In Neo-CheckRay, iSBRT (24 Gy in three 8-Gy fractions) was delivered to the primary tumor only, sparing the ipsilateral breast and regional nodes, and was given in all three arms to isolate the added effect of immunotherapy. An exploratory dose analysis found that the pCR benefit from adding checkpoint inhibition was preserved only when the axilla received less than 1 Gy (27.1% increase); no benefit was seen when axillary dose exceeded 1 Gy, consistent with preclinical data suggesting that irradiating tumor-draining lymph nodes can blunt immunotherapy efficacy.

Paired baseline and week 6 biopsies, obtained 1 week after iSBRT, showed evidence of tumor microenvironment reprogramming toward a more inflamed phenotype in the checkpoint inhibitor arms, including upregulation of major histocompatibility complex class I expression, increased PD-L1 expression on immune cells, and downregulation of stromal CD73—changes most evident in PD-L1–negative tumors. Despite this mechanistic rationale, the addition of oleclumab did not improve outcomes over durvalumab alone.

Grade 3 or higher treatment-related adverse events occurred in 29.2% of patients receiving iSBRT and chemotherapy alone, compared with 64.7% and 70.8% in the single ICI and double ICI arms, respectively, reflecting the added toxicity burden of immunotherapy rather than new safety signals. Immune-mediated adverse events of any grade occurred in 49.0% and 43.7% of patients in the single ICI and double ICI arms, most commonly thyroid dysfunction. No treatment-related deaths occurred, and iSBRT did not compromise the feasibility of breast-conserving surgery.

The authors, led by Alex De Caluwé, MD, of Institut Jules Bordet in Brussels, Belgium, noted that the trial's small sample size and use of iSBRT across all arms preclude isolating the individual contributions of radiation, paclitaxel, and immunotherapy to the observed effects. Event-free survival data remain immature, with planned analyses at 3 and 5 years after surgery. The findings support further investigation of radiotherapy as a strategy to sensitize immunologically cold ER+/HER2− breast tumors to checkpoint blockade, the authors concluded.

REFERENCES

1. 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. Published online June 25, 2026. doi:10.1038/s41591-026-04453-z

2. Cardoso F, O'Shaughnessy J, Liu Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2− breast cancer: a randomized phase 3 trial (KEYNOTE-756; NCT03725059). Nat Med. 2025;31(2):442-448. doi:10.1038/s41591-024-03415-7

3. Loi S, Salgado R, Curigliano G, et al. Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial (CheckMate 7FL; NCT04109066). Nat Med. 2025;31(2):433-441. doi:10.1038/s41591-024-03414-8