Atezolizumab, Paclitaxel, Trastuzumab, and Pertuzumab in Treating Patients with HER2 Positive Breast Cancer That Is Locally Recurrent, Metastatic, or Cannot Be Removed by Surgery

Inclusion Criteria

• Women diagnosed with pathologically confirmed HER2-overexpressing breast cancer, that is locally recurrent, unresectable or metastatic (negative or positive for ER/PR, and positive for HER2)
• HER2 status confirmed positive by means of immunohistochemistry (IHC) or in situ hybridization (ISH) according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines; it is considered positive if scored as 3+ by an IHC method defined as uniform membrane staining for HER2 in 10% or more of tumor cells or demonstrate HER2 gene amplification by an ISH method (single probe, average HER2 copy number >= 6.0 signals/cell; dual probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0 signals/cell; dual probe HER2/chromosome enumeration probe (CEP)17 ratio >= 2.0 with an average HER2 copy number < 4.0 signals/cell; HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell)
• Have measurable clinical disease: measurable disease, defined as at least 1 measurable lesion on a CT scan as defined by RECIST (version v1.1)
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Hemoglobin >= 8 g/dL
• Platelets >= 100 x 10^9/L
• Serum bilirubin =< 1.5 x upper normal limit (UNL), except patients with Gilbert's syndrome
• Serum alanine aminotransferase (ALT) =< 2 x UNL or =< 5.0 x UNL in case of liver metastases
• Serum aspartate aminotransferase (AST) =< 2 x UNL or =< 5.0 x UNL in case of liver metastases
• Serum creatinine < 140 umol/L (< 1.6 mg/dL) or 1.5 x the upper limit of normal, whichever is less
• Serum alkaline phosphatase (ALP) =< UNL or =< 2.5 x ULN in case of liver and bone metastases
• Left ventricular ejection fraction of 50% or more at baseline (by echocardiography or multiple-gated acquisition scanning)
• Patients may have received one prior hormonal treatment for metastatic disease
• Patients may have received adjuvant or neoadjuvant chemotherapy with or without trastuzumab and pertuzumab with an interval greater than 12 months since completion of adjuvant/neoadjuvant treatment
• Patients who have received standard of care cycle 1 (one loading dose of trastuzumab and pertuzumab plus up to three weekly doses of weekly paclitaxel) as long as they can be enrolled and start cycle #2 with no more than 7 days of delay from the time of projected day 1 cycle 2 of treatment (day 22 + 0-7 days) date based on the time of initiation of cycle 1 day 1
• Patients may have received trastuzumab emtansine (TDM-1) (Kadcyla [registered trademark]) in adjuvant setting
• Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document
• Female participants of childbearing age must be willing to use contraception methods, or abstain from sexual activity throughout the course of the study and for 7 months after the last dose of trastuzumab and/or pertuzumab and/or atezolizumab
• Have provided tissue from a newly obtained biopsy obtained from a focus of metastatic disease (an archival tissue sample may be substituted if new biopsy cannot be obtained and by discretion of sponsor investigator)

Exclusion Criteria

• Patients participating in another trial of an investigational agent within 4 weeks of the 1st dose of the study
• Patients with tumors that cannot be measured or clinically followed
• Patients who had received therapy for metastatic breast cancer (other than that described above)
• Patients with active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 4 weeks prior to trial treatment
• Patients with any baseline grade 2 neuropathy
• Patients with known prior hypersensitivity reaction to any of the study drugs
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, etc), with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids ** No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• Diagnosis of immunosuppression or receiving steroid therapy or other immunosuppressive therapy within 4 weeks of the study
• Have evidence of interstitial lung disease or active, non-infectious pneumonitis
• Evidence of active tuberculosis
• Significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• Patients with human immunodeficiency virus (HIV1/2); an HIV test must be performed to confirm status prior to enrollment
• Patients who are carriers of hepatitis virus B and C; hepatitis B and C testing must be performed to confirm status prior to enrollment. Required hepatitis B tests include hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody
• Prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed cell death 1 ligand (PDL-1), anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
• Pregnant, breastfeeding, or expecting to conceive within the projected time of the trial, starting with the pre-screening or screening visit and through 7 months after the last dose of trial treatment
• Active infection requiring systemic therapy
• Active substance abuse or psychiatric disorders; in case, the patient falls under the lower spectrum of psychiatric disorders and is able to function well under medication, the patient could be accrued at the discretion of the physician
• The use of a RANKL inhibitor (denosumab) must be discontinued during the study; bisphosphonate therapy is permitted
• The following treatments must be discontinued: * Herbal medications * Immunomodulatory agents, including but not limited to interferons or interleukin (IL)-2 * Immunosuppressive medications, including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide * Systemic corticosteroids * Anti−tumor necrosis factor (TNF)-alpha agents
• Any live, attenuated vaccine within 28 days prior to the first day of treatment or during study treatment, or unwillingness to avoid live, attenuated vaccines within 5 months following the last dose of atezolizumab