A Study to Investigate Atezolizumab and Chemotherapy Compared With Placebo and Chemotherapy in the Neoadjuvant Setting in Participants With Early Stage Triple Negative Breast Cancer (IMpassion031)

Roche

Status and phase: Completed; Phase 3

Conditions: Triple-negative Breast Cancer

Treatments: Drug: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody; Drug: Cyclophosphamide; Drug: Filgrastim; Drug: Pegfilgrastim; Drug: Doxorubicin; Drug: Placebo; Drug: Nab-paclitaxel

Study type: Interventional

Funder types: Industry

Identifiers

NCT03197935

WO39392

2016-004734-22 (EudraCT Number)

Details and patient eligibility

About

This is a global Phase III, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of neoadjuvant treatment with atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1] antibody) and nab-paclitaxel followed by doxorubicin and cyclophosphamide (nab-pac-AC), or placebo and nab-pac-AC in participants eligible for surgery with initial clinically assessed triple-negative breast cancer (TNBC).

Enrollment: 333 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histologically documented TNBC (negative human epidermal growth factor receptor 2 [HER2], estrogen receptor [ER], and progesterone receptor [PgR] status)
• Confirmed tumor programmed death-ligand 1 (PD-L1) evaluation as documented through central testing of a representative tumor tissue specimen
• Primary breast tumor size of greater than (>) 2 centimeters (cm) by at least one radiographic or clinical measurement
• Stage at presentation: cT2-cT4, cN0-cN3, cM0
• Participant agreement to undergo appropriate surgical management including axillary lymph node surgery and partial or total mastectomy after completion of neoadjuvant treatment
• Baseline left ventricular ejection fraction (LVEF) greater than or equal to (>=) 53 percent (%) measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans
• Adequate hematologic and end-organ function
• Representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in paraffin blocks (preferred) or at least 20 unstained slides, with an associated pathology report documenting ER, PgR, and HER2 negativity
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm
• Women who are not postmenopausal or have undergone a sterilization procedure must have a negative serum pregnancy test result within 14 days prior to initiation of study drug

Exclusion criteria

• Prior history of invasive breast cancer
• Stage 4 (metastatic) breast cancer
• Prior systemic therapy for treatment and prevention of breast cancer
• Previous therapy with anthracyclines or taxanes for any malignancy
• History of ductal carcinoma in situ (DCIS), except for participants treated exclusively with mastectomy >5 years prior to diagnosis of current breast cancer
• History of pleomorphic lobular carcinoma in situ (LCIS), except for participants surgically managed >5 years prior to diagnosis of current breast cancer
• Bilateral breast cancer
• Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes
• 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 with a negligible risk of metastasis or death
• Cardiopulmonary dysfunction
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells
• Known allergy or hypersensitivity to the components of the formulations of atezolizumab, nab-paclitaxel, cyclophosphamide, or doxorubicin, filgrastim or pegfilgrastim
• Active or history of autoimmune disease or immune deficiency diseases except history of autoimmune-related hypothyroidism, controlled Type 1 diabetes mellitus, and dermatologic manifestations of eczema, psoriasis, lichen simplex chronicus, or vitiligo (e.g., participants with psoriatic arthritis are excluded)
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Positive human immunodeficiency virus (HIV) test at screening
• Active hepatitis B and hepatitis C virus infection
• Active tuberculosis
• Severe infections within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment, except prophylactic antibiotics
• Major surgical procedure within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study
• Prior allogeneic stem cell or solid organ transplantation
• Administration of a live attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk from treatment complications
• Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint-blockade therapies, including anti-cluster of differentiation 40 (anti-CD40), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment
• Treatment with systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medications during the study
• History of cerebrovascular accident within 12 months prior to randomization
• Pregnant or lactating, or intending to become pregnant during the study

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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333 participants in 2 patient groups, including a placebo group

Atezolizumab and Chemotherapy

Experimental group

Description:

Participants received atezolizumab (840 milligrams \[mg\]) via intravenous (IV) infusion every 2 weeks in combination with nab-paclitaxel (125 milligrams per square meter \[mg/m\^2\]) via IV infusion every week for 12 weeks, followed by atezolizumab (840 mg) every 2 weeks in combination with doxorubicin (60 mg/m\^2) and cyclophosphamide (600 mg/m\^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants continued to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by IV infusion every 3 weeks for 11 doses, for a total of approximately 12 months of atezolizumab therapy.

Treatment:

Drug: Pegfilgrastim

Drug: Doxorubicin

Drug: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody

Drug: Cyclophosphamide

Drug: Nab-paclitaxel

Drug: Filgrastim

Placebo and Chemotherapy

Placebo Comparator group

Description:

Participants received placebo matched to atezolizumab via IV infusion every 2 weeks in combination with nab-paclitaxel (125 mg/m\^2) via IV infusion every week for 12 weeks, followed by placebo matched to atezolizumab every 2 weeks in combination with doxorubicin (60 mg/m\^2) and cyclophosphamide (600 mg/m\^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants will be unblinded post-surgery and will continue to be followed.

Treatment:

Drug: Pegfilgrastim

Drug: Doxorubicin

Drug: Cyclophosphamide

Drug: Placebo

Drug: Nab-paclitaxel

Drug: Filgrastim