A Study To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer

A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer

This study (also known as IMpassion050) will evaluate the efficacy and safety of atezolizumab compared with placebo when given in combination with neoadjuvant dose-dense anthracycline (doxorubicin) + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) in patients with early HER2-positive breast cancer (T2-4, N1-3, M0).

Inclusion Criteria:

• Confirmed diagnosis of HER2-positive breast cancer, and hormonal and PD-L1 status, as documented through central testing of a representative tumor tissue specimen
• Primary breast tumor size of > 2 cm by any radiographic measurement
• Stage at presentation: T2-T4, N1-N3, M0 as determined by AJCC staging system, 8th edition
• Pathologic confirmation of nodal involvement with malignancy must be determined by fine needle aspiration or core-needle biopsy. Surgical excision of lymph nodes is not permitted.
• Patients with multifocal tumors are eligible provided at least one focus is sampled and centrally confirmed as HER2-positive.
• Patients with multicentric tumors are eligible provided all discrete lesions are sampled and centrally confirmed as HER2-positive.
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Baseline LVEF >= 55% measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans
• Adequate hematologic and end-organ function obtained within 14 days prior to initiation of study treatment
• For women of childbearing potential: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating eggs
• For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria:

• Prior history of invasive breast cancer
• Stage IV (metastatic) breast cancer
• Patients with synchronous bilateral invasive breast cancer
• Prior systemic therapy for treatment of breast cancer
• Previous therapy with anthracyclines or taxanes for any malignancy
• Ulcerating or inflammatory breast cancer
• Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes
• Sentinel lymph node procedure or axillary lymph node dissection prior to initiation of neoadjuvant therapy
• History of other malignancy within 5 years prior to screening, with the exception of those patients who have a negligible risk of metastasis or death
• Cardiopulmonary dysfunction
• Dyspnea at rest
• Active or history of autoimmune disease or immune deficiency
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab/placebo, 6 months after the final dose of doxorubicin, 12 months after the final dose of cyclophosphamide, 6 months after the final dose of paclitaxel, or 7 months after the final dose of trastuzumab, pertuzumab, or trastuzumab emtansine whichever occurs last

Exclusion Criteria Related to Trastuzumab Emtansine in the Adjuvant Setting:

• Patients who achieved pCR
• Evidence of clinically evident gross residual or recurrent disease following neoadjuvant therapy and surgery
• Unable to complete surgery with curative intent after conclusion of neoadjuvant systemic therapy
• Patient discontinued treatment with trastuzumab because of toxicity during the neoadjuvant phase of the study
• Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, or sclerosis cholangitis
• Patients with Grade >=2 peripheral neuropathy
• Prior treatment with trastuzumab emtansine