ASTEFENIA (Katherine)

Patients must meet the following criteria for study entry:

· Signed Informed Consent Form

· Age > 18 years at time of signing the Informed Consent Form

· Ability to comply with the study protocol

· Histologically confirmed invasive breast carcinoma

· Clinical stage at presentation (as per American Joint Committee on Cancer [AJCC] Cancer Staging Manual, 8th edition): cT4/anyN/M0, any cT/N2–3/M0, or cT1-3/N0-1/M0 (patients with cT1mi/T1a/T1b/N0 are not eligible) including the following requirements:

- Patients with cT1-3/N0-1/M0 disease at presentation (patients with cT1mi/T1a/T1b/N0 are not eligible) must have pathologic evidence of residual invasive carcinoma in axillary lymph node(s) at surgery (with or without residual invasive disease in the breast)

- Patients with cT4/anyN/M0 or any cT/N2–3/M0 disease at presentation must have pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph node(s) at surgery

· Diagnosis of HER2-positive breast cancer with assessment of hormone receptor and PD-L1 status, as documented through central testing of a representative tumor tissue specimen from a pretreatment (prior to neoadjuvant therapy) biopsy

Tissue requirements:

- A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred), or at least 20 slides containing unstained, freshly cut, serial sections must be submitted prior to study enrollment.

o Patients with synchronous bilateral invasive disease or multicentric tumors (multiple tumors involving more than one quadrant) are eligible provided that all discrete lesions are centrally confirmed as HER2-positive.

For patients with multifocal tumors (more than one mass confined to the same quadrant as the primary tumor), at least one focus must be sampled and centrally confirmed as HER2-positive. Refer to Appendix 3 for detailed tissue sample requirements.

§ In patients with multifocal or multicentric breast cancer, the largest lesion should be measured to determine T stage.

For patients with multicentric disease, if sufficient pretreatment biopsy material is not available from all discrete lesions, the postoperative histology from all residual breast lesions must be centrally confirmed as HER2-positive.

o Preferably, pretreatment breast biopsy material will be assessed to centrally determine HER2, PD-L1, ER, and PgR status. In the event that sufficient material from the pretreatment biopsy is not available, central biomarker assessment may be performed on residual tumor tissue obtained at the time of definitive surgery.

o Any deviations from the material requirements are only allowed after Medical Monitor approval has been obtained.

- HER2-positive status will be determined and is defined as an immunohistochemistry (IHC) score of 3 + or a positive result as measured by in situ hybridization (ISH), prospectively assessed prior to study enrollment.

ISH positivity is defined as a ratio of ³ 2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies. Patients will be eligible provided that at least one HER2 test (IHC or ISH) yields a positive result.

o HER2 IHC and ISH assays will be performed by a central laboratory using Ventanaâ PATHWAY anti-HER2/neu [4B5] Rabbit Monoclonal Primary Antibody and Ventanaâ HER2 Dual ISH DNA Probe Cocktail. Detailed usage instructions and scoring criteria are specified in the package inserts for these products, which are available upon request.

- PD-L1 status will be assessed by IHC using the Ventanaâ PD-L1 (SP142) assay; positive status is defined by PD-L1 expression on IC for ³ 1% of the tumor area (IC 1/2/3), negative status is defined by PD-L1 expression on IC for < 1% of the tumor area (IC 0). The maximum PD-L1 score assessed among submitted samples during screening will be used as the PD-L1 score for the patient.

- Hormone receptor (ER and PgR) status will be determined centrally according to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists guidelines.

· Completion of preoperative systemic chemotherapy and HER2-directed treatment

- Systemic therapy must consist of at least 6 cycles with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane-based chemotherapy. Patients may have received an anthracycline as part of preoperative therapy in addition to taxane-based chemotherapy.

- Patients receiving dose-dense chemotherapy regimens are eligible, provided at least 6 weeks of taxane-based therapy and at least 8 weeks of trastuzumab have been given. A dose-escalated (225 mg/m2 every 2 weeks) dose-dense regimen of paclitaxel over 6 weeks is allowed.

Patients may have received more than one HER2-directed therapy (e.g., trastuzumab + pertuzumab).

- All systemic chemotherapy must be completed preoperatively.

· Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes, defined as follows:

Breast surgery:

- Total mastectomy with no gross residual disease at the margin of resection, or breast-conserving surgery with histologically negative margins of excision.

- For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected

margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.

Lymph node surgery:

- In case of positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy performed prior to preoperative therapy, additional surgical evaluation of the axilla following preoperative therapy is required.

- If only micrometastases are present in sentinel nodes preoperatively (i.e., if the greatest diameter of the nodal metastasis in a sentinel node is 0.2 mm or less), no additional surgical evaluation of the axilla is required.

- If sentinel node biopsy performed before preoperative therapy was negative, no additional surgical evaluation of the axilla is required after preoperative therapy.

- If the only sentinel node identified by isotope scan is in the internal mammary chain, surgical evaluation of the axilla is recommended.

- If sentinel node biopsy performed after preoperative therapy is positive, additional surgical evaluation of the axilla is recommended.

- If sentinel node evaluation after preoperative therapy is negative, no further additional surgical evaluation of the axilla is required.

- Axillary dissection without sentinel node evaluation is permitted after preoperative therapy.

· An interval of no more than 12 weeks between the date of primary surgery and the date of randomization

· Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

· Screening left ventricular ejection fraction (LVEF) ³ 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan after completion of neoadjuvant therapy and no decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF. Alternatively, if the pre-chemotherapy LVEF was not assessed, the screening LVEF must be ³ 55% after completion of neoadjuvant therapy.

· Life expectancy ³ 6 months

· Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to randomization:

- ANC ³ 1.5 x 109/L (1500 cells/μL) without granulocyte colony-stimulating factor (G-CSF) support

- Lymphocyte count ³ 0.5 x 109/L (500 cells/μL)

- Platelet count ³ 100,000 cells/μL without transfusion

- Hemoglobin ³ 9.0 g/dL

o Patients may receive red blood cell transfusions to obtain this level

- Creatinine clearance ³ 30 mL/min (calculated using the Cockcroft-Gault formula)

- INR and aPTT £ 1.5 ´ upper limit of normal (ULN)

o For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

- Serum AST and ALT £ 1.5 ´ ULN

- Serum ALP £ 2.5 x ULN

- Serum total bilirubin (TBILI) £ 1.0 ´ ULN (within normal limits), except for patients with Gilbert’s syndrome, for whom direct bilirubin should be within the normal range

- Serum albumin ³ 25 g/L (2.5 g/dL)

- For premenopausal women including women who have had a tubal ligation and for women < 12 months after the onset of menopause, negative serum pregnancy test

· Negative HIV test at screening with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ³ 200/μL, have an undetectable viral load and provided that they

have not had a history of AIDS-defining opportunistic infections within 12 months prior to randomization. Investigators need to consider potential drug-drug interactions between study treatment and anti-retroviral therapies before enrolling patients (see Section 4.4.2.2).

· Negative hepatitis B surface antigen (HBsAg) test at screening

· Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following:

- Negative total hepatitis B core antibody (HBcAb)

- Positive total HBcAb test followed by a negative (per local laboratory definition) hepatitis B virus (HBV) DNA test

Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening

- The HCV RNA test is only required for patients who have a positive HCV antibody test.

· For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or to use contraception, and agreement to refrain from donating eggs, as defined below:

- Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final dose of atezolizumab/placebo and for 7 months after the final dose of trastuzumab emtansine or trastuzumab, whichever occurs last. Women must refrain from donating eggs during this same period.

- A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (³ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.

- Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, copper intrauterine devices, hormonal contraceptives that inhibit ovulation, and hormone-releasing intrauterine devices in women with hormone receptor-negative tumors only; the use of hormonal contraceptives and hormone releasing intrauterine devices are

prohibited in women with hormone receptor-positive tumors.

- The reliability of sexual abstinence should be evaluated in relation to the duration of study treatment and the preferred and usual lifestyle of the patient.

Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.

If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.

· For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

- With a female partner of childbearing potential who is not pregnant, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 7 months after the final dose of trastuzumab emtansine or trastuzumab, whichever occurs last. Men must refrain from donating sperm during this same period.

With a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 7 months after the final dose of trastuzumab emtansine or trastuzumab to avoid exposing the embryo.

- The reliability of sexual abstinence should be evaluated in relation to the duration of study treatment and the preferred and usual lifestyle of the patient.

Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. 

Patients who meet any of the following criteria will be excluded from study entry:

· Stage IV (metastatic) breast cancer

· Inadequate excision (as described under Section 4.1.1)

· An overall response of disease progression according to the investigator at the conclusion of preoperative systemic therapy

· Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation)

· History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or DCIS

· History of exposure to the following cumulative doses of anthracyclines:

- Doxorubicin > 240 mg/m2

- Epirubicin or liposomal doxorubicin-hydrochloride (Myocetâ) > 480 mg/m2

- For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m2

· Prior treatment with trastuzumab emtansine or atezolizumab

· Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

· Current NCI CTCAE v5.0 Grade ³ 2 peripheral neuropathy

· Dyspnea at rest

· Cardiopulmonary dysfunction as defined by any of the following:

- History of NCI CTCAE v5.0 Grade ³ 3 symptomatic heart failure or New York Heart Association (NYHA) criteria Class ³ II

- Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease

High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular (AV)-block (second-degree AV-block Type 2 [Mobitz 2] or third degree AV-block)

- Significant symptoms (Grade ³ 2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative therapy

- History of a decrease in LVEF to < 40% during prior trastuzumab treatment (e.g., during preoperative therapy)

- Myocardial infarction within 12 months prior to randomization

- Uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg)

- Evidence of transmural infarction on ECG

- Requirement for continuous oxygen therapy

· 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 (see Appendix 8 for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions:

- Patients with a history of autoimmune-related hypothyroidism who are on a stable dose of thyroid-replacement hormone are eligible for the study.

- Patients with controlled type 1 diabetes mellitus who are on a stable 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:

o Rash must cover < 10% of body surface area

o Disease is well controlled at baseline and requires only low-potency topical corticosteroids.

o 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.

· History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis

- History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

· Active tuberculosis

· Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders; ulcers)

Any known active liver disease, for example, autoimmune hepatic disorders, or sclerosing cholangitis

· Major surgical procedure, other than for breast cancer, within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the study

· Severe infection within 4 weeks prior to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, severe pneumonia, infection with SARS-CoV-2, or any active infection that, in the opinion of the investigator, could affect patient safety

· Treatment with therapeutic antibiotics within 2 weeks (IV antibiotics) or 5 days (oral antibiotics) prior to randomization

- Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease [COPD] exacerbation) are eligible for the study.

· Prior allogeneic stem cell or solid organ transplantation

· Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug and may affect the interpretation of the results, or may render the patient at high risk from

treatment complications

· Treatment with a live, attenuated vaccine within 4 weeks prior to randomization, or anticipation of need for such a vaccine during atezolizumab/placebo treatment or within 5 months after the final dose of atezolizumab/placebo

· Treatment with investigational therapy within 28 days prior to randomization

· Treatment with systemic immunostimulatory agents (including but not limited to interferon and IL-2) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to randomization

· Treatment with systemic immunosuppressive medication (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-a [TNF-a] agents) within 2 weeks prior to randomization,

or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

- Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor approval has been obtained.

- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

· History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation

· History of intolerance, including Grade 3 or 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product

· Pregnant or breastfeeding, or intending to become pregnant during study treatment or within 5 months after the final dose of atezolizumab/placebo or within 7 months after the final dose of trastuzumab emtansine or trastuzumab, whichever occurs last

- Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to randomization. 

Research Nurse: Emma Davies (Ext No. 55649) Emma.Davies16@nhs.net

Administrator: Arun Prakash