PRIMARY OBJECTIVE:
I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the
progression-free survival (PFS), assessed by investigator using Response Evaluation Criteria
in Solid Tumors (RECIST) 1.1 criteria, relative to the addition of a placebo to a regimen of
pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) in patients with
newly documented HER2-positive measurable metastatic breast cancer.
SECONDARY OBJECTIVES:
I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the overall
survival (OS) relative to the addition of placebo to a regimen of pertuzumab and trastuzumab,
combined with a taxane (paclitaxel or docetaxel).
II. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the overall
objective response (OR), assessed by investigator using RECIST 1.1 criteria, relative to the
addition of placebo to a regimen of pertuzumab and trastuzumab combined with a taxane
(paclitaxel or docetaxel).
III. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve PFS, OR, and/or
duration of objective response assessed by retrospective blinded central review using RECIST
1.1 criteria, relative to the addition of placebo to a regimen of pertuzumab and trastuzumab
combined with a taxane (paclitaxel or docetaxel).
IV. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
trastuzumab combined with a taxane (paclitaxel or docetaxel) will decrease the incidence of
subsequent brain metastases in patients without known brain metastases at study entry
relative to the addition of placebo to a regimen of pertuzumab and trastuzumab combined with
a taxane (paclitaxel or docetaxel).
V. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
trastuzumab combined with a taxane (paclitaxel or docetaxel) will contribute to increased
patient-reported fatigue in comparison to the addition of placebo to a regimen of pertuzumab
and trastuzumab combined with a taxane (paclitaxel or docetaxel).
VI. To determine the utility of PD-L1 immunohistochemistry (IHC) staining as a predictive and
prognostic biomarker associated with clinical response, as assessed by investigator using
RECIST 1.1 criteria, to atezolizumab in combination with trastuzumab and pertuzumab combined
with a taxane (paclitaxel or docetaxel).
VII. To determine the immune-related toxicity profile of the two treatment regimens.
VIII. To determine the cardiac safety profile of the two treatment regimens.
EXPLORATORY OBJECTIVES:
I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and
trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the
progression-free survival and overall objective response, assessed by investigator using
immune-modified RECIST (iRECIST) criteria, relative to the addition of a placebo to a regimen
of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).
II. To identify potential biomarkers that can predict benefit from the addition of
atezolizumab in patients with newly documented HER2-positive measurable metastatic breast
cancer treated with a regimen of pertuzumab and trastuzumab combined with a taxane
(paclitaxel or docetaxel).
III. To explore the toxicity profile of the two treatment regimens using patient-reported
symptomatic adverse events in addition to standard adverse event reports.
IV. To determine the feasibility and added value of frequent assessment of toxicity using
Patient Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) with
electronic(e)PRO reporting.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive pertuzumab intravenously (IV) over 30-60 minutes on days 1 and 22,
trastuzumab IV over 30-90 minutes on days 1 and 22, and paclitaxel IV over 60 minutes on days
1, 8, 15, 22, 29, and 36 or docetaxel IV over 60 minutes on days 1 and 22. Cycles repeat
every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also
receive atezolizumab IV over 30-60 minutes on day 1 of cycle 1 and days 1 and 22 of
subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease
progression or unacceptable toxicity.
ARM II: Patients receive pertuzumab, trastuzumab, and paclitaxel or docetaxel as in Arm I.
Patients also receive placebo IV 30-60 minutes on day 1 of cycle 1 and days 1 and 22 of
subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 3 years and
then every 6 months for 4 years.
Inclusion Criteria:
- The patient must have signed and dated an Institutional Review Board (IRB)-approved
consent form that conforms to federal and institutional guidelines
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1
- Histologically confirmed adenocarcinoma of the breast with locally recurrent,
unresectable disease or metastatic disease outside the central nervous system (CNS)
confirmed as described below; eligible patients include those with either:
- De novo metastatic disease presenting without prior history of HER2-positive
breast cancer:
- Diagnosis should have been made from a biopsy of a metastatic disease site,
but biopsy from the breast primary or involved regional lymph nodes is
acceptable if biopsy of the metastatic sites was thought to carry excessive
risk for the patient
- Locally recurrent or metastatic disease following prior therapy for early breast
cancer:
- Diagnosis must have been made from the biopsy of the locally recurrent or
metastatic disease
- There must be an interval of >= 6 months between completion of
neoadjuvant/adjuvant HER2-targeted therapy and documentation of locally
recurrent or metastatic HER2-positive disease by biopsy
- Patients must have measurable disease based on RECIST 1.1, as determined by the site,
which has not been irradiated to be eligible
- Patients with brain metastases are eligible if they meet ALL the following criteria:
- Four or fewer metastatic sites to CNS
- Largest unexcised tumor does not exceed 3 cm
- No metastases to brain stem, midbrain, pons, medulla or the optic nerves and
chiasm
- Must have measurable disease outside the CNS, based on RECIST 1.1, as determined
by the site, which has not been irradiated
- If patient presented with symptoms from CNS metastases, the symptoms must have
resolved with initiation of steroids and initial local therapy (surgery,
radiation therapy, or both)
- Must have been evaluated by Medical Oncologist and plan is to administer
trastuzumab, pertuzumab, and a taxane as first-line systemic therapy
- May have received administration of trastuzumab OR lapatinib concurrently with
radiation therapy for brain metastases. Toxicities related to lapatinib if
administered, should be
- =< grade 1 per the CTCAE v5.0, and the lapatinib must have been completed at
least 2 weeks prior to study entry
- No history of intracranial hemorrhage or spinal cord hemorrhage
- No neurosurgical resection or brain biopsy within 10 days prior to study entry
- After study entry and before randomization, send tissue for central HER2 confirmation;
a tumor specimen obtained at the time of diagnosis of locally recurrent or metastatic
disease must have been determined to be HER2-positive based on local testing according
to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)
guidelines (Wolff 2018); HER2 status should initially be assessed using an Food and
Drug Administration (FDA)-cleared IHC assay; positive is defined as IHC 3+ staining
intensity; if HER2 IHC results are equivocal (2+), then HER2 status will be determined
using a FDA-cleared HER2 in situ hybridization (ISH) test according to ASCO/CAP
guidelines; Note: Once HER2-positive is confirmed on central testing, patients will be
randomized to atezolizumab/placebo; randomization within 14 days from study entry will
ensure that the Pharmaceutical Management Branch (PMB)-supplied agents will be
received at the site for treatment on day 22 of cycle 1
- The tumor specimen obtained at the time of diagnosis used for HER2 testing must also
have central testing for PD-L1 status; patients will be eligible irrespective of PD-L1
testing result including PD-L1 indeterminant
- The tumor specimen obtained at the time of diagnosis used for HER2 and PD-L1 testing
should also have central testing for estrogen receptor (ER) and progesterone receptor
(PgR) according to current ASCO/CAP guideline recommendations for hormone receptor
testing; patients with < 1% ER and PgR staining by IHC will be classified as negative;
if enough material for central confirmation of ER and PgR is unavailable, local
testing results for ER and PgR may be used for eligibility
- Localized palliative radiation therapy to sites of non-measurable disease is allowed
for symptom management and may begin prior to study entry and continue following study
entry while receiving study therapy
- Patients must have imaging of the chest/abdomen/pelvis, preferably with a computed
tomography (CT) scan, and a bone scan within 5 weeks prior to study entry; (NOTE: if a
patient is unable to receive CT contrast, a magnetic resonance imaging [MRI] of the
abdomen/pelvis and non-contrast chest CT should be performed; positron emission
tomography/computed tomography [PET/CT] is not an acceptable alternative)
- MRI of the brain (or contrast CT scan of the brain if patients are unable to undergo
MRI) must be obtained in patients with symptoms suggesting possible central nervous
system (CNS) metastatic disease; neuroimaging is recommended but not required in
asymptomatic patients
- Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 14 days prior to study
entry)
- Platelet count must be >= 100,000/mm^3 (within 14 days prior to study entry)
- Hemoglobin must be >= 8 g/dL (within 14 days prior to study entry)
- Total bilirubin must be =< 1.5 x upper limit of normal (ULN) for the lab or direct
bilirubin =< ULN for patients with bilirubin levels > 1.5 x ULN (within 14 days prior
to study entry)
- Aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) must be =< 2.5 x
ULN for the lab or =< 5 x ULN for patients with liver metastases (within 14 days prior
to study entry)
- Serum creatinine =< 1.5 x ULN or measured or calculated creatinine clearance >= 50
mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x
ULN for the lab (within 14 days prior to study entry)
- Patients not receiving anti-coagulant therapy must have prothrombin time (PT) and
international normalized ratio (INR) =< 1.5 x ULN within 14 days prior to study entry;
for laboratories that do not report an ULN for the INR assay, use =< 1.5 as the value
for the ULN; patients receiving anti-coagulants should have a baseline INR assessed,
but the value does not affect eligibility
- A serum thyroid-stimulating hormone (TSH) and AM (preferably in morning) cortisol must
be obtained within 14 days prior to study entry to obtain a baseline value; patients
with abnormal TSH or AM cortisol baseline levels should be further evaluated and
managed per institutional standards; asymptomatic patients who require initiation or
adjustment of medication or are followed without initiating treatment based on
endocrinologist's recommendations are eligible
- Left ventricular ejection fraction (LVEF) assessment must be performed within 6 weeks
prior to study entry; (LVEF assessment performed by echocardiogram is preferred;
however, multigated acquisition scan (MUGA) scan may be substituted based on
institutional preferences); the LVEF must be >= 50% regardless of the cardiac imaging
facility's lower limit of normal
- Administration of atezolizumab may have an adverse effect on pregnancy and poses a
risk to the human fetus, including embryo-lethality; women of child-bearing potential
and men must agree to use adequate contraception (non-hormonal or barrier method of
birth control; abstinence) prior to study entry, for the duration of study
participation, and for 5 months (150 days) after the last dose of atezolizumab/placebo
and 7 months after the last dose of trastuzumab and pertuzumab; should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she should inform her treating physician immediately
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of study entry are eligible for
this trial
Exclusion Criteria:
- Patients with brain metastases are excluded if they meet ANY of the following
criteria:
- Symptoms from brain metastases have not resolved prior to study entry
- Five or more clearly identified foci of metastases to the brain
- Largest unexcised tumor exceeds 3 cm
- Spinal cord metastases
- Medical Oncologist plans to employ HER2-directed tyrosine kinase inhibitor as
component of systemic therapy
- Metastatic disease limited to CNS
- Leptomeningeal carcinomatosis
- History of systemic anti-cancer therapy (e.g., chemotherapy, targeted therapy) for
metastatic breast cancer (MBC) except as described in inclusion criteria
- History of exposure to cumulative doses of doxorubicin greater than 360 mg per square
meter of body-surface area or its equivalent
- Prior treatment with mTOR inhibitors or CDK 4/6 inhibitors in combination with
endocrine therapy for treatment of metastatic disease
- Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including
anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- History of non-breast malignancies (except for in situ cancers treated only by local
excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior
to study entry
- Uncontrolled hypertension defined as sustained systolic blood pressure (BP) > 150 mmHg
or diastolic BP > 90 mmHg; (patients with initial BP elevations are eligible if
initiation or adjustment of BP medication lowers pressure to meet entry criteria)
- History of asymptomatic LVEF decline to < 40% during or after prior HER2-targeted
therapy even if the current LVEF is >= 50%
- Cardiac disease (history of and/or active disease) that would preclude the use of the
drugs included in the treatment regimens; this includes but is not confined to:
- Active cardiac disease
- Angina pectoris that requires the current use of anti-anginal medication;
- Ventricular arrhythmias except for benign premature ventricular
contractions;
- Supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication;
- Conduction abnormality requiring a pacemaker;
- Valvular disease with documented compromise in cardiac function; or
- Symptomatic pericarditis
- History of cardiac disease
- Prior myocardial infarction documented by elevated cardiac enzymes or
persistent regional wall abnormalities on assessment of left ventricular
(LV) function;
- History of documented congestive heart failure (CHF) defined as symptomatic
heart failure with an LVEF < 40%; or
- Documented cardiomyopathy
- Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
sensory neuropathy) >= grade 2, per the CTCAE v 5.0
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
pertuzumab or trastuzumab or to any of its excipients, as well as any chimeric or
humanized antibodies or fusion proteins
- Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells
or other recombinant antibodies
- Known allergy or hypersensitivity to the components of the atezolizumab formulation or
to any of the study drugs or excipients, (e.g., Cremophor EL, polysorbate 80)
- History or risk of autoimmune disease, including, but not limited to, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis
- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible
- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible
- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations
- Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled at baseline and only requiring low-potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
- No acute exacerbations of underlying conditions within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids)
- Treatment with systemic immunosuppressive medications (including but not limited to
interferons, IL-2) within 4 weeks or 5 half-lives of the drug, whichever is longer,
prior to study entry
- Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis [anti-TNF] factor agents) within 14 days prior to study entry or anticipation
of need for systemic immunosuppressive medications during the study; Note: Intranasal
and inhaled corticosteroids or systemic corticosteroids at doses that do not exceed 10
mg/day of prednisone or an equivalent corticosteroid are allowed
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 2 weeks prior to study entry
- Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B
surface antigen (HBsAg) test at screening; patients with a past or resolved HBV
infection, defined as having a negative HBsAg test and a positive total hepatitis B
core antibody (HBcAb) test at screening, are eligible for the study if active HBV
infection is ruled out on the basis of HBV deoxyribonucleic acid (DNA) viral load per
local guidelines
- Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV
ribonucleic acid (RNA)
- Patients with clinically active tuberculosis
- Severe infection within 4 weeks prior to study entry, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia
- Prior allogeneic stem cell or solid organ transplantation
- Symptomatic peripheral ischemia
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis or >= grade 1 pulmonary fibrosis, per the CTCAE v5.0, on screening chest
CT scan
- Administration of a live, attenuated vaccine within 4 weeks prior to study entry or
anticipati
