RT→pembrolizumab (PD-1) preop window yields higher major pathologic response than pembrolizumab→RT in early breast cancer

Pembrolizumab is an anti–PD-1 immune checkpoint inhibitor, and this Phase 1b/2 multi-arm adaptive “window-of-opportunity” study (NCT04454528) tested whether a single 7Gy RT fraction sequenced before vs after a single preop pembrolizumab 200mg dose could improve short-interval response ahead of upfront surgery in early-stage breast cancer (n=30; Arm 1 RT→pembro n=14, Arm 2 pembro→RT n=11, Arm 3 pembro alone n=5). All patients proceeded to surgery without delay; there were no grade ≥3 AEs and one grade 2 immune-related AE (hypothyroidism). Imaging tumor shrinkage >30% (TΔ30) was 57.1% (8/14) with RT→pembro and 54.5% (6/11) with pembro→RT vs 0% (0/5) with pembro alone, and in TNBC was 85.7% (6/7) and 66.7% (4/6) vs 0% (0/4); major pathologic response (RCB 0/1) favored RT→pembro at 50% (7/14) vs 10% (1/10) with pembro→RT and 0% (0/4) with pembro alone (TNBC: 57% [4/7] vs 0% [0/5] vs 0% [0/3]). Relative to current TNBC neoadjuvant SOC—pembrolizumab + multi-agent chemotherapy with pCR ~65% vs ~51% with chemo alone in KEYNOTE-522—this chemo-free, single-dose/single-fraction approach shows intriguing short-term activity but is not yet benchmarked to pCR/EFS outcomes or an optimized systemic regimen.