Neoadjuvant HER2-targeted therapy with or without immunotherapy with pembrolizumab (neoHIP): An open label randomized phase II trial

Abstract

Abstract 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) is 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, HER2-directed therapy with ICI administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxic backbones; 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). This randomized, multicenter, phase II, open-label trial, will evaluate the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K (NCT03747120). Trial design 174 patients (pts) ≥18y with previously untreated, clinical stage II-III, HER2+ breast cancer will be randomized 1:1:1 to one of the 3 arms, stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive THP: T at 80mg/m2 weekly for 12 weeks, H day 1 at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P day 1 at 840mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K day 1 at 200mg (flat dose) and then every 3 weeks x 3 doses (THP-K). In arm C, pts receive TH-K. Definitive surgery is 3-6 weeks after the last dose of T. After surgery, pts are treated per the treating physician's discretion including HER2-directed therapy and radiotherapy per local clinical standards. 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 identification NCT03747120. Legal entity responsible for the study The authors. Funding Breast Cancer Research Foundation, Merck & Co. Disclosure H.L. McArthur: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Immunomedics; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Genomic Health; Research grant / Funding (institution): ZIOPHARM Oncology; Travel / Accommodation / Expenses: Puma Biotechnology. J.H.S. Leal: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca. D.B. Page: Honoraria (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dohme; Advisory / Consultancy: Syndax; Advisory / Consultancy: Nektar; Advisory / Consultancy: NanoString Technologies; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Puma Biotechnology; Speaker Bureau / Expert testimony: Genentech/Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: MedImmune; Speaker Bureau / Expert testimony: Philips Healthcare. A. Bardia: Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Radius Health; Advisory / Consultancy, Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Innocrin; Advisory / Consultancy, Research grant / Funding (institution): Biothernostics Inc.; Advisory / Consultancy: Spectrum Pharma; Advisory / Consultancy: Taiho; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Daiichi Pharma. L. Spring: Advisory / Consultancy: Novartis; Advisory / Consultancy: Lumicell; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution): Tesaro. R.K. Basho: Advisory / Consultancy: Puma Biotech; Advisory / Consultancy: Heron Therapeutics. S. Verma: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Puma; Advisory / Consultancy: Novartis; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Mylan. All other authors have declared no conflicts of interest.