Background: Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with increased therapeutic efficacy of trastuzumab in the (neo)adjuvant setting for HER2-positive breast cancer (BC). Subcutaneous (SC) trastuzumab has been observed to act at different immunologic levels than IV trastuzumab. Therefore, by modifying the modality of administration of trastuzumab, it could be possible to interfere with different pathways of the immune system and exert a favorable immunomodulation in HER2-positive BC.

Trial design: In this non-comparative, phase II, neoadjuvant, randomized study, patients will be treated with FEC chemotherapy (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; cyclophosphamide 500 mg/m2) q21 for 3 cycles. Then, they will be randomly assigned in a 1:1 ratio to receive: docetaxel (75 mg/m2) plus pertuzumab (840 mg loading dose, then 420 mg) plus IV trastuzumab (8 mg/kg loading dose, then 6 mg/kg) q21 for 4 cycles (Group A) or, docetaxel plus pertuzumab plus SC trastuzumab (fixed dose of 600 mg) q21 for 4 cycles (Group B). After surgery, study patients will receive trastuzumab q21 x 14 cycles using the same formulation (SC or IV) of the preoperative phase.

Eligibility criteria: Patients must have previously untreated, T2-4d primary HER2-positive BC with no metastatic disease. Other inclusion criteria are: age 18 or older; ECOG performance status 0-1; availability of tumor tissue from diagnostic biopsy; normal left ventricular ejection fraction; normal organ and marrow function.

Specific aims: The main objective of this trial is to evaluate variations of host immune response parameters to either trastuzumab SC or trastuzumab IV given in combination with pertuzumab and chemotherapy as neoadjuvant treatment of patients with HER2-positive BC. Tumor samples obtained at diagnosis and at definitive surgery will be centrally analyzed for TILs. Blood samples will be also collected during study treatment for tumor-specific lymphocyte cell activity (TLA) analysis. Feasibility, efficacy, safety and health-related quality of life will be also evaluated.

Statistical methods: The primary endpoint is post-surgery pathologic TIL rate on residual disease. The threshold for classifying subjects with high TILs, or not, is defined as equal to 15%, according to the median TIL rate observed in primary HER2-positive tumors. Because this is a phase II study with 2 non-comparative arms, Simon's optimal 2-stage design will be used for each of the 2 study groups. For each arm we assume: p1 = 0.4, expected rate of subjects with high TILs on residual disease, p0 = 0.1, lowest limit of the subject rate (alpha= 0.05; beta= 0.20).

Present accrual and target accrual: A total of 60 patients (first stage: 16 patients) will be enrolled from multiple institutions. From November 29, 2016 to June 11, 2017, 34 patients have been recruited.

Contact information:Dr. Antonino Musolino, MD, MSc, PhD; Medical Oncology Unit, University Hospital of Parma; Tel: +390521702316; Fax: +390521995448; e-mail: amusolino@ao.pr.it. Clinical Trials.gov: NCT03144947.

Citation Format: Musolino A, Gori S, Cavanna L, Graiff C, Frassoldati A, Bria E, Bisagni G, Zambelli A, Partesotti G, Brandes A, Bonetti A, Moscetti L, Zamagni C, Rocca A, Generali D, Montemurro F, Gianni L, Tognetto M, Maglietta G, Todeschini R. Phase II, open label, randomized, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with operable or locally advanced/Inflammatory HER2-positive breast cancer. ImmunHER trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-03.