Breast Cancer
Conditions
Keywords
Nivolumab, Breast Cancer, Cancer, Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor 2 Negative (HER2-), Neoadjuvant, Adjuvant, Primary Breast Cancer
Brief summary
A randomized multi-arm study evaluating the efficacy and safety of nivolumab versus placebo in combination with neoadjuvant (pre-surgery) chemotherapy and adjuvant (post-surgery) endocrine therapy in participants with high-risk, estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) early stage breast cancer.
Interventions
BIOLOGICALnivolumab
Specified Dose on Specified days
DRUGpaclitaxel (PTX)
Specified dose on Specified days
OTHERnivolumab placebo
Specified dose on Specified days
DRUGanthracycline
Specified dose on Specified days
DRUGcyclophosphamide
Specified dose on Specified days
DRUGEndocrine Therapy
Variable endocrine therapy of investigators choice
PROCEDURESurgery
Surgery for breast cancer
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Localized invasive breast ductal carcinoma, confirmed by the local pathologist, that includes the following combined primary tumor and clinical node (cN) categories: T1c (tumor size = 2 cm)-T2 (tumor size \> 2 cm), cN1-N2 OR T3-T4, cN0-cN2. Note: Axillary lymph node status must be assessed by fine needle biopsy or core biopsy. * Estrogen receptor-positive (ER+) breast cancer (BC) and with or without progesterone receptor (PgR) expression (determined on the most recently analyzed tissue sample, tested locally, and confirmed by the central laboratory), as defined in the relevant American Society of Clinical Oncology (ASCO)- College of American Pathologists (CAP) Guidelines. * Human epidermal growth factor receptor 2 (HER2-) BC tested in the local laboratory, defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+, or 2+. * Tumor Grade 3 of ductal histology, Or Tumor Grade 2 of ductal histology having an ER expression level percentage between 1-10% * Must agree to provide primary breast tumor tissue at baseline and at surgery * Must be deemed eligible for surgery * Males and females must agree to follow specific methods of contraception, if applicable, while participating in the trial * Must have an Eastern Cooperative Oncology Group (ECOG) scale performance status of 0 or 1
Exclusion criteria
* Breastfeeding, pregnant, or expecting to conceive or father children within the projected duration of the study, starting with the screening through 12 months for participants who receive cyclophosphamide, or 6 months for participants who do not receive cyclophosphamide, after the last dose of study treatment * Prior treatment with chemotherapy, endocrine therapy (ET), targeted therapy, and/or radiation therapy for the currently diagnosed breast cancer prior to enrollment * Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways * Significant cardiovascular disease such as left ventricular ejection fraction (LVEF) \< 50% at baseline as assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan performed at screening, or Class III or IV myocardial disease as described by the New York Heart Association * History of ipsilateral invasive BC, regardless of treatment, ipsilateral ductal carcinoma in situ treated with radiation, or contralateral invasive BC, at any time * Definitive clinical or radiologic evidence of metastatic disease * Multicentric BC (the presence of \> 1 tumor in different quadrants of the breast) * Bilateral invasive BC Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) Rate | Up to approximately 37 months | pCR rate is defined as the percentage of participants who achieved pCR. pCR is defined as no invasive residual disease in breast and lymph nodes performed by a local pathologist. Criteria for evaluation of pCR includes the following: pCR in breast, axillary lymph nodes and non-axillary sentinel node; no histologic evidence of invasive tumor cells; and pCR in the breast. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Residual Cancer Burden (RCB) | Up to approximately 37 months | RCB is estimated from routine pathologic sections of the primary breast tumor site and the regional lymph nodes after the completion of neoadjuvant therapy. RCB is categorized into the following 4 classes: RCB-0: no residual disease; RCB-1: minimal residual disease; RCB-II: moderate residual disease; RCB-III: and extensive residual disease. |
| Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | Up to approximately 37 months | RCB is estimated from routine pathologic sections of the primary breast tumor site and the regional lymph nodes after the completion of neoadjuvant therapy. RCB is categorized into the following 4 classes: RCB-0: no residual disease; RCB-1: minimal residual disease; RCB-II: moderate residual disease; RCB-III: and extensive residual disease. |
| Pathological Complete Response (pCR) Rate (PD-L1 >=1%) | Up to approximately 37 months | pCR rate is defined as the percentage of participants who achieved pCR. pCR is defined as no invasive residual disease in breast and lymph nodes performed by a local pathologist. Criteria for evaluation of pCR includes the following: pCR in breast, axillary lymph nodes and non-axillary sentinel node; no histologic evidence of invasive tumor cells; and pCR in the breast. |
| Number of Participants With Serious Adverse Events (SAEs) | From first dose to 30 days post last dose of neoadjuvant or adjuvant study therapy (Up to approximately 19 months) | Number of participants with any grade serious adverse events (SAE). SAE is defined as any untoward medical occurrence that, at any dose: Results in death; is life threatening; requires inpatient hospitalization; results in persistent or significant disability; is a congenital anomaly/birth defect. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
| Number of Participants Who Died | Up to approximately 41 months | Number of participants who died due to any cause. |
| Number of Participants With Adverse Events (AEs) | From first dose to 30 days post last dose of neoadjuvant or adjuvant study therapy (Up to approximately 19 months) | Number of participants with any grade adverse events (AEs). An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment that does not necessarily have a causal relation with this treatment. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Czechia, Denmark, Finland, France, Germany, Hong Kong, Ireland, Italy, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Romania, Russia, Singapore, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
2 Participants planned for Arm B treatment received Arm A treatment.
Participants by arm
| Arm | Count |
|---|---|
| Arm A Neoadjuvant (Pre-surgery) Phase 8 cycles maximum:
Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): Nivolumab 360 mg Q3W + PTX QW
Followed by:
Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = Q2W or Q3W):
Nivolumab 360 mg Q3W + AC Q3W or Nivolumab 240 mg Q2W + AC Q2W
Surgery and Adjuvant (Post-surgery) Phase 7 cycles maximum:
Adjuvant Cycles 1-7 (1 cycle = Q4W):
Nivolumab 480 mg Q4W + Endocrine Therapy (ET) | 263 |
| Arm B Neoadjuvant (Pre-surgery) Phase 8 cycles maximum:
Paclitaxel (PTX) Cycles 1-4 (1 cycle = Q3W): Nivolumab Placebo Q3W + PTX QW
Followed by:
Anthracycline-Cyclophosphamide (AC) Cycles 1-4 (1 cycle = Q2W or Q3W):
Nivolumab Placebo Q3W + AC Q3W or Nivolumab Placebo Q2W + AC Q2W
Surgery and Adjuvant (Post-surgery) Phase 7 cycles maximum:
Adjuvant Cycles 1-7 (1 cycle = Q4W):
Endocrine Therapy (ET) | 258 |
| Total | 521 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pre-treatment | Participant no longer meets study criteria | 1 | 1 |
| Pre-treatment | Participant withdrew consent | 2 | 0 |
| Treatment | Administrative reasons by sponsor | 2 | 3 |
| Treatment | Adverse Event | 23 | 7 |
| Treatment | Adverse Event unrelated to Study drug | 1 | 0 |
| Treatment | Death | 3 | 0 |
| Treatment | Disease Progression | 4 | 7 |
| Treatment | Disease Recurrence | 0 | 2 |
| Treatment | Lack of Efficacy | 2 | 4 |
| Treatment | Not reported | 4 | 8 |
| Treatment | Other reasons | 17 | 23 |
| Treatment | Participant no longer meets study criteria | 2 | 2 |
| Treatment | Participant request to discontinue Study treatment | 15 | 14 |
| Treatment | Study drug toxicity | 12 | 5 |
| Treatment | Withdrawal by Subject | 8 | 8 |
Baseline characteristics
| Characteristic | Arm B | Total | Arm A |
|---|---|---|---|
| Age, Continuous | 50.9 Years STANDARD_DEVIATION 11.8 | 50.4 Years STANDARD_DEVIATION 11.9 | 49.9 Years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 80 Participants | 154 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 121 Participants | 223 Participants | 102 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 57 Participants | 144 Participants | 87 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 17 Participants | 35 Participants | 18 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 42 Participants | 24 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 14 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 30 Participants | 11 Participants |
| Race (NIH/OMB) White | 193 Participants | 395 Participants | 202 Participants |
| Sex: Female, Male Female | 257 Participants | 519 Participants | 262 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 129 | 7 / 136 | 4 / 124 | 4 / 132 |
| other Total, other adverse events | 126 / 127 | 132 / 135 | 120 / 123 | 130 / 132 |
| serious Total, serious adverse events | 38 / 127 | 51 / 135 | 20 / 123 | 26 / 132 |
Outcome results
Primary
Pathological Complete Response (pCR) Rate
pCR rate is defined as the percentage of participants who achieved pCR. pCR is defined as no invasive residual disease in breast and lymph nodes performed by a local pathologist. Criteria for evaluation of pCR includes the following: pCR in breast, axillary lymph nodes and non-axillary sentinel node; no histologic evidence of invasive tumor cells; and pCR in the breast.
Time frame: Up to approximately 37 months
Population: All randomized participants with sufficient follow-up for pCR assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Pathological Complete Response (pCR) Rate | 24.5 Percentage of participants |
| Arm B | Pathological Complete Response (pCR) Rate | 13.8 Percentage of participants |
Comparison: Arm A over Arm Bp-value: 0.002195% CI: [1.29, 3.27]Cochran-Mantel-Haenszel
95% CI: [4, 16.9]
Secondary
Number of Participants Who Died
Number of participants who died due to any cause.
Time frame: Up to approximately 41 months
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Participants Who Died | 15 Participants |
| Arm B | Number of Participants Who Died | 8 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
Number of participants with any grade adverse events (AEs). An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment that does not necessarily have a causal relation with this treatment. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: From first dose to 30 days post last dose of neoadjuvant or adjuvant study therapy (Up to approximately 19 months)
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Number of Participants With Adverse Events (AEs) | Adverse Events (AEs) | 259 Participants |
| Arm A | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 254 Participants |
| Arm A | Number of Participants With Adverse Events (AEs) | AEs leading to discontinuation | 41 Participants |
| Arm B | Number of Participants With Adverse Events (AEs) | Adverse Events (AEs) | 252 Participants |
| Arm B | Number of Participants With Adverse Events (AEs) | Drug-Related AEs | 236 Participants |
| Arm B | Number of Participants With Adverse Events (AEs) | AEs leading to discontinuation | 14 Participants |
Secondary
Number of Participants With Residual Cancer Burden (RCB)
RCB is estimated from routine pathologic sections of the primary breast tumor site and the regional lymph nodes after the completion of neoadjuvant therapy. RCB is categorized into the following 4 classes: RCB-0: no residual disease; RCB-1: minimal residual disease; RCB-II: moderate residual disease; RCB-III: and extensive residual disease.
Time frame: Up to approximately 37 months
Population: All randomized participants with sufficient follow-up for RCB assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Number of Participants With Residual Cancer Burden (RCB) | RCB-I | 17 Participants |
| Arm A | Number of Participants With Residual Cancer Burden (RCB) | RCB-III | 57 Participants |
| Arm A | Number of Participants With Residual Cancer Burden (RCB) | RCB-II | 90 Participants |
| Arm A | Number of Participants With Residual Cancer Burden (RCB) | Not Reported | 31 Participants |
| Arm A | Number of Participants With Residual Cancer Burden (RCB) | RCB-0 | 62 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) | Not Reported | 20 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) | RCB-0 | 34 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) | RCB-I | 20 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) | RCB-II | 106 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) | RCB-III | 73 Participants |
Secondary
Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1%
RCB is estimated from routine pathologic sections of the primary breast tumor site and the regional lymph nodes after the completion of neoadjuvant therapy. RCB is categorized into the following 4 classes: RCB-0: no residual disease; RCB-1: minimal residual disease; RCB-II: moderate residual disease; RCB-III: and extensive residual disease.
Time frame: Up to approximately 37 months
Population: All randomized participants in PD-L1 expression on immune cells \>=1% subgroup with sufficient follow-up for RCB assessment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | RCB-I | 10 Participants |
| Arm A | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | RCB-III | 9 Participants |
| Arm A | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | RCB-II | 25 Participants |
| Arm A | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | Not Reported | 6 Participants |
| Arm A | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | RCB-0 | 38 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | Not Reported | 6 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | RCB-0 | 16 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | RCB-I | 6 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | RCB-II | 36 Participants |
| Arm B | Number of Participants With Residual Cancer Burden (RCB) PD-L1 >=1% | RCB-III | 20 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs)
Number of participants with any grade serious adverse events (SAE). SAE is defined as any untoward medical occurrence that, at any dose: Results in death; is life threatening; requires inpatient hospitalization; results in persistent or significant disability; is a congenital anomaly/birth defect. Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: From first dose to 30 days post last dose of neoadjuvant or adjuvant study therapy (Up to approximately 19 months)
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Number of Participants With Serious Adverse Events (SAEs) | 80 Participants |
| Arm B | Number of Participants With Serious Adverse Events (SAEs) | 45 Participants |
Secondary
Pathological Complete Response (pCR) Rate (PD-L1 >=1%)
pCR rate is defined as the percentage of participants who achieved pCR. pCR is defined as no invasive residual disease in breast and lymph nodes performed by a local pathologist. Criteria for evaluation of pCR includes the following: pCR in breast, axillary lymph nodes and non-axillary sentinel node; no histologic evidence of invasive tumor cells; and pCR in the breast.
Time frame: Up to approximately 37 months
Population: All randomized participants in PD-L1 expression on immune cells \>=1% subgroup with sufficient follow-up for pCR assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Pathological Complete Response (pCR) Rate (PD-L1 >=1%) | 44.3 Percentage of participants |
| Arm B | Pathological Complete Response (pCR) Rate (PD-L1 >=1%) | 20.2 Percentage of participants |
Comparison: Arm A over Arm B95% CI: [1.58, 6.11]
95% CI: [10.7, 37.5]