Background: In preclinical models HER2-directed therapy administered with checkpoint blockade is synergistic. Clinically, trastuzumab administered with pembrolizumab-mediated checkpoint blockade in trastuzumab-resistant HER2-positive metastatic breast cancer was safe and demonstrated modest activity. However, because checkpoint blockade can confer improved responses when administered earlier in the course of disease, trastuzumab with pembrolizumab administered in the curative-intent, treatment-naive setting may confer life-long, tumor-specific immunity and ultimately, improve cure rates. Moreover, the potential synergy of trastuzumab and pembrolizumab with paclitaxel may overcome the need for dual HER2-blockade. The neo-HIP study is a randomized, multicenter, phase II, open-label trial to evaluate the efficacy and safety of weekly paclitaxel, trastuzumab plus pertuzumab (THP) vs weekly THP plus pembrolizumab (THP-K) vs a HER2 monotherapy regimen (TH-K) as neoadjuvant treatment in patients with HER2-positive early stage invasive breast cancer.

Methods:Patients ≥18 years old with previously untreated, non-metastatic, stage II-III, HER2-positive (by ASCO/CAP guidelines) breast cancer are eligible. Patients with inflammatory breast cancer or bilateral primary tumors are excluded. Adequate organ function and ECOG PS 0-1 are required. Approximately 174 patients will be randomly assigned to 1 of 3 arms with stratification by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, patients will receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (1 loading dose) and then 6mg/Kg IV every 3 weeks x 3 doses, P at 840mg (1 loading dose) and then 420mg/Kg IV every 3 weeks x 3 doses (THP). In arm B, patients will receive the same regimen as arm A with the addition of pembrolizumab 200mg IV every 3 weeks x 4 doses (THP-K). In arm C, patients will receive the same regimen as arm B, but without pertuzumab (TH-K). Definitive surgery will be 3-6 weeks after the last treatment dose. After surgery, patients in all arms willbe treated per the treating physician's discretion. After completion of post-operative chemotherapy, patients will receive radiotherapy per local clinical standard and those patients whose tumors are hormone-receptor positive will receive hormone therapy as per local standard-of-care. The purpose of this phase II study is to identify whether Arm B (THP-K) and/or Arm C (TH-K) demonstrate a clinically significant improvement in pCR rate when compared with Arm A (THP). The primary end point is 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 the immunologic responses to the interventions and explore potential predictors of efficacy and toxicity.

Citation Format: McArthur HL, Leal JHS, DiLauro Abaya C, Basho R, Coleman H, Shiao S, Knott S, Tighiouart M, Dadmanesh F, Giuliano A, Verma S. Neoadjuvant Her2-targeted therapy +/- immunotherapy with pembrolizumab (neoHIP): An open label randomized phase II trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-02.