NIMBUS: Nivolumab Plus Ipilimumab in Metastatic Hypermutated HER2-negative Breast Cancer

• ClinicalTrials.gov Identifier: NCT03789110
• Recruitment Status: Active, not recruiting
• First Posted: December 28, 2018
• Results First Posted: September 27, 2022
• Last Update Posted: December 13, 2023
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Sara Tolaney, MD, Dana-Farber Cancer Institute

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Nivolumab; Drug: Ipilimumab
• Enrollment: 30

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Nivolumab+Ipilimumab
Arm/Group Description	Ipilimumab is administered intravenously every 6 weeks; Nivolumab is administered intravenously every 2 weeks Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
Period Title: Overall Study
Started	30
Completed	0
Not Completed	30
Reason Not Completed
Adverse Event	2
Physician Decision	1
Withdrawal by Subject	2
Lack of Efficacy	22
still on treatment	3

Baseline Characteristics

Arm/Group Title		Nivolumab+Ipilimumab
Arm/Group Description		Ipilimumab is administered intravenously every 6 weeks; Nivolumab is administered intravenously every 2 weeks Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
Overall Number of Baseline Participants		30
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	21 70.0%
	>=65 years	9 30.0%
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	30 participants
		63; (36 to 72)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	Female	30 100.0%
	Male	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	American Indian or Alaska Native	0 0.0%
	Asian	1 3.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	27 90.0%
	More than one race	2 6.7%
	Unknown or Not Reported	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	30 participants
		30
ECOG Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	0	22 73.3%
	1	8 26.7%
		[1] Measure Description: The ECOG (Eastern Cooperative Oncology Group) Scale of Performance Status describes a patient's level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working, etc.). This is a numbering scale of 0 to 5. The higher the number, the worse the performance status. Zero (0) refers to being full active. 5 is dead.
Hormone Receptor (HR) Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	HR +	21 70.0%
	Triple Negative	9 30.0%
		[1] Measure Description: HR+ is defined as ER (Estrogen receptors) positive, or PR (progesterone receptors) positive, or Her2 positive Triple negative is defined as ER negative, and PR negative, and Her2 negative
Prior lines of chemotherapy in the advanced setting; Median (Full Range); Unit of measure: Line
	Number Analyzed	30 participants
		1.5; (0 to 3)
PD-L1 positive cells; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants
	Positive	4 13.3%
	Negative	21 70.0%
	Missing sample	4 13.3%
	Specimen not adequate for evaluation	1 3.3%
TMB (mut/Mb) [1]; Median (Full Range); Unit of measure: mut/Mb
	Number Analyzed	30 participants
		10.9; (9 to 110)
		[1] Measure Description: TMB: Tumor mutational burden

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate of Nivolumab in Combination With Ipilimumab
Description	Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The analysis population includes all patients who initiated protocol therapy

Arm/Group Title	Nivolumab+Ipilimumab
Arm/Group Description:	Ipilimumab is administered intravenously every 6 weeks; Nivolumab is administered intravenously every 2 weeks Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
Overall Number of Participants Analyzed	30
Measure Type: Count of Participants; Unit of Measure: Participants
	5 16.7%

2. Secondary Outcome

Title	Overall Response Rate of the Combination According to Immune-related Response Criteria
Description	Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by immune-related response criteria (irRC). Per irRC: irComplete Response (irCR): Complete disappearance of all tumor lesions (target an non-target) together with no new measurable/unmeasurable lesions for at least 4 weeks from the date of documentation of complete response. Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular diameters of all target lesions is measured and captured as the SPD baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular diameters of all target lesions and of new measurable lesions are added together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline, of the irSPD compared to the previously SPD baseline of 50% or greater is considered an irPR.; Overall Response (OR) = irCR + irPR.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

all patients who initiated protocol therapy

Arm/Group Title	Nivolumab+Ipilimumab
Arm/Group Description:	Ipilimumab is administered intravenously every 6 weeks; Nivolumab is administered intravenously every 2 weeks Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
Overall Number of Participants Analyzed	30
Measure Type: Count of Participants; Unit of Measure: Participants
	6 20.0%

3. Secondary Outcome

Title	Clinical Benefit Rate
Description	Clinical Benefit Rate (CBR) will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 24 weeks, per RECIST 1.1
Time Frame	2 Years

Outcome Measure Data

Analysis Population Description

analysis population includes all patients who initiated protocol therapy

Arm/Group Title	Nivolumab+Ipilimumab
Arm/Group Description:	Ipilimumab is administered intravenously every 6 weeks; Nivolumab is administered intravenously every 2 weeks Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
Overall Number of Participants Analyzed	30
Measure Type: Count of Participants; Unit of Measure: Participants
	5 16.7%

4. Secondary Outcome

Title	Progression Free Survival
Description	Progression free survival is defined from the study entry to first documented evidence of disease progression by RECIST 1.1 or death of any cause, whichever occurs first. Patients alive with no progression are censored at the last disease assessment.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

all patients who initiated protocol therapy

Arm/Group Title	Nivolumab+Ipilimumab
Arm/Group Description:	Ipilimumab is administered intravenously every 6 weeks; Nivolumab is administered intravenously every 2 weeks Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
Overall Number of Participants Analyzed	30
Median (95% Confidence Interval); Unit of Measure: month
	1.4; (1.3 to 4.6)

5. Secondary Outcome

Title	Overall Survival
Description	OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
Time Frame	Participants were followed long-term for survival every 12 weeks from the end of treatment until death or lost to follow-up. Median follow-up in this study cohort was 9.7 months.

Outcome Measure Data

Analysis Population Description

All patients who initiated protocol therapy

Arm/Group Title	Nivolumab+Ipilimumab
Arm/Group Description:	Ipilimumab is administered intravenously every 6 weeks; Nivolumab is administered intravenously every 2 weeks Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
Overall Number of Participants Analyzed	30
Median (95% Confidence Interval); Unit of Measure: month
	19.3 [1]; (5.2 to NA)

[1]

Follow-up is not long enough/data is not mature to provide upper bound confidence interval.

Adverse Events

Time Frame	AE data were collected every cycle from the time of the first dose of the study treatment, through the end of the treatment. Vital status was followed even after patients were off treatment. AEs, including overall mortality, were observed up to 30 months.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Nivolumab+Ipilimumab
Arm/Group Description	Ipilimumab is administered intravenously every 6 weeks; Nivolumab is administered intravenously every 2 weeks Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
All-Cause Mortality
	Nivolumab+Ipilimumab
	Affected / at Risk (%)
Total	13/30 (43.33%)
Serious Adverse Events
	Nivolumab+Ipilimumab
	Affected / at Risk (%)
Total	5/30 (16.67%)
Cardiac disorders
Atrial fibrillation † 1	1/30 (3.33%)
Myocarditis † 1	1/30 (3.33%)
Eye disorders
Eyelid function disorder † 1	1/30 (3.33%)
Investigations
Cardiac troponin T increased † 1	1/30 (3.33%)
Platelet count decreased † 1	1/30 (3.33%)
Metabolism and nutrition disorders
Anorexia † 1	1/30 (3.33%)
Hypokalemia † 1	1/30 (3.33%)
Hyponatremia † 1	1/30 (3.33%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify † 1	1/30 (3.33%)
Nervous system disorders
Lethargy † 1	1/30 (3.33%)
Myasthenia gravis † 1	1/30 (3.33%)
Psychiatric disorders
Confusion † 1	1/30 (3.33%)
Respiratory, thoracic and mediastinal disorders
Hypoxia † 1	1/30 (3.33%)
Pneumonitis † 1	1/30 (3.33%)
1 Term from vocabulary, CTCAE (5.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Nivolumab+Ipilimumab
	Affected / at Risk (%)
Total	24/30 (80.00%)
Blood and lymphatic system disorders
Anemia † 1	3/30 (10.00%)
Endocrine disorders
Hypothyroidism † 1	2/30 (6.67%)
Gastrointestinal disorders
Diarrhea † 1	4/30 (13.33%)
Mucositis oral † 1	2/30 (6.67%)
General disorders
Fatigue † 1	9/30 (30.00%)
Pain † 1	3/30 (10.00%)
Investigations
Alanine aminotransferase increased † 1	2/30 (6.67%)
Aspartate aminotransferase increased † 1	2/30 (6.67%)
Neutrophil count decreased † 1	2/30 (6.67%)
Metabolism and nutrition disorders
Anorexia † 1	2/30 (6.67%)
Musculoskeletal and connective tissue disorders
Back pain † 1	3/30 (10.00%)
Bone pain † 1	2/30 (6.67%)
Pain in extremity † 1	2/30 (6.67%)
Respiratory, thoracic and mediastinal disorders
Dyspnea † 1	2/30 (6.67%)
1 Term from vocabulary, CTCAE (5.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Sara Tolaney
• Organization: Dana-Farber Cancer Institute
• Phone: 617-632-5743
• EMail: Sara_Tolaney@dfci.harvard.edu

• Responsible Party: Sara Tolaney, MD, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03789110
• Other Study ID Numbers: 18-561
• First Submitted: December 26, 2018
• First Posted: December 28, 2018
• Results First Submitted: August 30, 2022
• Results First Posted: September 27, 2022
• Last Update Posted: December 13, 2023