Primary results from the triple-negative cohort of TBCRC-053 (P-RAD): A randomized trial of no, low, or high dose preoperative radiation with pembrolizumab and chemotherapy in node-positive breast cancer.

1011 Background: Approximately one-quarter of patients with node-positive, triple-negative breast cancer (TNBC) did not experience a complete nodal response to neoadjuvant chemo-immunotherapy in KEYNOTE-522. We conducted a randomized trial to evaluate whether no-, low-, or high-dose preoperative radiotherapy (RT) to the breast primary tumor combined with pembrolizumab (pembro) enhances tumor T-cell infiltration (TCI) and pathologic response in non-irradiated lymph node (LN) metastases (NCT04443348). Methods: Between 2021-2025, 55 patients with cT1c-T4c, cN1-3, cM0, ER/PR < 10%, HER2-negative breast cancer and biopsy-proven, clipped axillary LN metastasis were randomized to no RT (0 Gy), low-dose RT (9 Gy) or high-dose RT (24 Gy) to the primary tumor with concurrent pembro, followed by an on-treatment tumor biopsy at 2 wks. Stratification factors included cT stage (T1c vs. T2-4) and cN stage (N1 vs. N2-3). Patients subsequently received pembro (200 mg q3w or 400 mg q6w) with 12 wks of paclitaxel/carboplatin, followed by four cycles of doxorubicin-cyclophosphamide (q2w or q3w) with pembro, surgery and adjuvant therapy. Primary endpoints were 2-wk tumor TCI and nodal pathologic complete response (ypN0) at surgery. TCI was assessed by multiplexed immunofluorescence (panCK/CD3/CD8) using a rank-based Immunoscore. 2-wk TCI for each treatment arm was compared to a common reference cohort of pretreatment TCI measurements. The study was powered to detect an increase in upper-quartile TCI from 25% to 55%. Statistical comparisons used two-tailed Fisher’s exact tests. ypN0 and secondary endpoints pCR (ypT0/TisN0) and Residual Cancer Burden (RCB) 0/1 were underpowered for a statistical test. Results: Among 55 enrolled patients, 48 were evaluable for TCI and 51 for ypN0. Median age was 50 years (range 28-77). 81.8% had cT2-4 disease, 20% had cN2-3, and 87.3% had grade 3 tumors. The proportion of tumors with upper-quartile TCI was significantly increased with RT plus pembro, but not pembro alone, when compared to the pretreatment cohort: 44% (0Gy; p = NS), 80% (9Gy, p < 0.0001), and 82% (24Gy; p < 0.0001). ypN0 rates were 73.3% (0Gy), 88.2% (9Gy) and 78.9% (24Gy). pCR/RCB 0-1 rates were 66.6%/66.6% (0Gy), 76.5%/82.4% (9Gy) and 68.4%/84.2% (24Gy). Tumors with upper-quartile TCI at the 2-wk timepoint had a significantly higher ypN0 rate relative to tumors without upper-quartile TCI (94% [31/33] vs. 46% [6/13]; p = 0.0009). Conclusions: The addition of preoperative RT to pembro significantly increased 2-wk TCI and yielded high rates of ypN0 and pCR after chemo-immunotherapy, with the numerically highest ypN0 rate observed in the 9Gy arm. 2-wk TCI correlated strongly with surgical ypN0 status. A larger study that tests whether preoperative RT and pembro increases pCR should be conducted in node-positive TNBC. Clinical trial information: NCT04443348 .