Nivolumab + Ipilimumab for Breast Cancer

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Brain metastases, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 18

Duration: 9.7 months

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must stop any chemotherapy, biologic therapy, or other anti-cancer treatments at least 14 days before starting the trial. You can continue bisphosphonate therapy if you are already on it.

What data supports the effectiveness of the drug combination of Nivolumab and Ipilimumab for breast cancer?

Research shows that the combination of Nivolumab and Ipilimumab has been effective in treating other cancers, like lung cancer and melanoma, by improving survival rates and reducing tumor size. This suggests potential benefits for breast cancer treatment, although direct evidence for breast cancer is not yet available. ^{1 2 3 4 5}

Is the combination of Nivolumab and Ipilimumab safe for humans?

The combination of Nivolumab and Ipilimumab can cause more frequent and severe side effects compared to using Nivolumab alone. These side effects can include colitis (inflammation of the colon), pneumonitis (lung inflammation), and diarrhea. Most side effects are reversible with treatment, but close monitoring by experienced healthcare providers is important. ^{6 7 8 9 10}

How does the drug combination of Nivolumab and Ipilimumab differ from other breast cancer treatments?

The combination of Nivolumab and Ipilimumab is unique because it uses two immune checkpoint inhibitors to enhance the body's immune response against cancer cells, which is different from traditional chemotherapy that directly targets cancer cells. This approach is part of a growing trend in breast cancer treatment to use immunotherapy, especially in cases where other treatments have limited effectiveness. ^{11 12 13 14 15}

What is the purpose of this trial?

This research study is studying a drug combination of nivolumab and ipilimumab as a possible treatment for hypermutated HER2 negative breast cancer. The drugs involved in this study are: * Nivolumab (Opdivo ®) * Ipilimumab (Yervoy ®)

Research Team

Sara Tolaney, MD, MPH

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults with metastatic HER2-negative breast cancer that's hypermutated (TMB ≥9 mutations/megabase). They can have had up to three prior chemo treatments and must be off chemo for at least 14 days. Participants need functioning major organs, no severe illnesses, not pregnant or breastfeeding, and agree to use effective contraception.

Inclusion Criteria

I have recovered from previous cancer treatment side effects, except for hair loss and numbness.

I am mostly able to care for myself and carry out daily activities.

My breast cancer is HER2-negative and may be hormone receptor positive or negative.

Exclusion Criteria

I have not received a live vaccine in the last 28 days.

I have not taken any other cancer treatments in the last 14 days.

I do not have any other cancer needing treatment at the same time.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab intravenously every 2 weeks and ipilimumab every 6 weeks

9.7 months

Bi-weekly visits for nivolumab, every 6 weeks for ipilimumab

Follow-up

Participants are monitored for overall survival and response rate every 12 weeks

2 years

Every 12 weeks

Treatment Details

Interventions

• Ipilimumab
• Nivolumab

Trial Overview The study tests a combination of two drugs: Nivolumab (Opdivo) and Ipilimumab (Yervoy), as potential treatment for this type of breast cancer. It includes patients who've tried other treatments without success and measures the effectiveness of these drugs in controlling the disease.

Participant Groups

Group I: Nivolumab+Ipilimumab Experimental Treatment 2 Interventions

* Ipilimumab is administered intravenously every 6 weeks * Nivolumab is administered intravenously every 2 weeks

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

Nivolumab combined with ipilimumab significantly improves treatment outcomes in cancer, showing higher rates of complete response (CR), partial response (PR), and overall response rate (ORR) compared to either drug alone, based on a meta-analysis of 11 studies.

While the combination therapy N1I3 (1 mg/kg nivolumab and 3 mg/kg ipilimumab) was more effective than N3I1 (3 mg/kg nivolumab and 1 mg/kg ipilimumab), it also had a higher incidence of serious adverse events, though overall safety was still considered acceptable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis. Chen, J., Li, S., Yao, Q., et al.[2021]

Combined immune checkpoint blockade (ICB) using nivolumab and ipilimumab shows significant efficacy in treating advanced melanoma, but it also leads to a higher frequency and severity of adverse drug reactions (ADRs) compared to single-agent therapies, based on pooled safety data from 1551 patients.

Most immune-related ADRs are reversible with glucocorticoids, but due to the increased risk and rapid onset of these toxicities, clinicians must be well-trained to monitor and manage these side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Hassel, JC., Heinzerling, L., Aberle, J., et al.[2022]

In a study analyzing 2,088 individual case safety reports (ICSRs) related to immune checkpoint inhibitors (ICIs) in Italy, 801 reports documented serious immune-related adverse drug reactions (irADRs), primarily affecting male patients with gastrointestinal and skin toxicities.

Among the ICIs, nivolumab and pembrolizumab were most frequently associated with irADRs, with significant risks identified for pembrolizumab and ipilimumab, highlighting the need for oncologists to recognize and manage these serious side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. Ruggiero, R., Fraenza, F., Scavone, C., et al.[2022]

A systematic review of 14 randomized controlled trials found that combining nivolumab (NIVO) with ipilimumab (IPI) significantly increases the risk of treatment-related adverse events (TRAEs) compared to NIVO alone, with an overall risk ratio of 1.11 for any grade TRAEs and 1.95 for severe (grade 3 or 4) TRAEs.

Specific adverse events were notably higher with the combination therapy, including colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68), indicating that while the combination may be effective, it comes with increased safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. Kamat, S., Patel, J., Brown, BR., et al.[2022]

Checkpoint immunotherapy is being explored as a new treatment for metastatic breast cancer, but single-agent therapies targeting PD1/PD-L1 or CTLA-4 have shown limited effectiveness.

Combining immunotherapy with other treatments like chemotherapy, radiotherapy, and targeted therapies may enhance cancer immunity and improve treatment outcomes, with ongoing clinical trials investigating these combination strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Strategies of Checkpoint Immunotherapy in Metastatic Breast Cancer. Liu, ZB., Zhang, L., Bian, J., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. [2023]

4. England pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. [2022]

10. China pubmed.ncbi.nlm.nih.gov

The efficacy and safety of PD-1/PD-L1 inhibitors in breast cancer: a systematic review and meta-analysis. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Immunotherapy Approaches for Breast Cancer Patients in 2023. [2023]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical trial data and emerging immunotherapeutic strategies: hormone receptor-positive, HER2- negative breast cancer. [2021]

13. England pubmed.ncbi.nlm.nih.gov

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

PD-L1 Protein Expression on Both Tumor Cells and Macrophages are Associated with Response to Neoadjuvant Durvalumab with Chemotherapy in Triple-negative Breast Cancer. [2021]

15. New Zealand pubmed.ncbi.nlm.nih.gov

Combination Strategies of Checkpoint Immunotherapy in Metastatic Breast Cancer. [2020]