Background: Immune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) was safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, H and K administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxics; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). In this randomized, multicenter, phase II, open-label trial the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K are explored. Methods: 174 patients (pts) ≥18y with previously untreated, stage II-III, HER2+ breast cancer will be randomized and stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P at 840 mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K at 200mg every 3 weeks x 4 doses (THP-K). In arm C, pts receive TH-K. Definitive surgery is 3-6 weeks after the last dose. After surgery, pts are treated per the treating physician’s discretion including radiotherapy per local clinical standard. Pts whose tumors are hormone-receptor positive will receive hormone therapy per local standard-of-care. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Clinical trial information: NCT03747120.