Nivolumab + Relatlimab + Ipilimumab for Renal Cell Carcinoma

Overseen By Eric Jonasch, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: CNS metastases, Autoimmune disease, Myocarditis, 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: 3

Duration: 12 months

15 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on certain treatments like corticosteroids above a specific dose or other immunosuppressive medications within 14 days before starting the trial.

What data supports the effectiveness of the drug combination Nivolumab, Relatlimab, and Ipilimumab for treating renal cell carcinoma?

Research shows that the combination of Nivolumab and Ipilimumab is effective for treating advanced renal cell carcinoma, with studies demonstrating improved survival rates compared to other treatments. This combination has been approved for use in patients with intermediate or poor-risk advanced renal cell carcinoma. ^{1 2 3 4 5}

Is the combination of Nivolumab, Relatlimab, and Ipilimumab safe for treating renal cell carcinoma?

The combination of Nivolumab and Ipilimumab has been studied for safety in renal cell carcinoma, showing manageable safety with some patients experiencing serious side effects. Common side effects include immune-related adverse events, which can be serious but are often manageable with medical care. ^{6 7 8 9 10}

How is the drug combination of Nivolumab, Relatlimab, and Ipilimumab unique for treating renal cell carcinoma?

This drug combination is unique because it combines three immune checkpoint inhibitors, which work by helping the immune system recognize and attack cancer cells more effectively. Nivolumab and Ipilimumab have already shown improved survival rates in advanced renal cell carcinoma compared to traditional treatments, and the addition of Relatlimab may enhance this effect further. ^{1 2 11 12 13}

What is the purpose of this trial?

This is a phase 2 stratified, randomized, multicenter, study investigating the efficacy of a triplet arm treating with nivolumab 480 mg every 4 weeks (Q4W), relatlimab 160 mg Q4W and ipilimumab 1 mg/kg every 8 weeks (Q8W) intravenous (IV) versus a doublet arm treating with nivolumab 480 mg Q3W and ipilimumab 1mg/kg Q3W IV in first-line advanced RCC.

Research Team

Eric Jonasch, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with advanced kidney cancer (Renal Cell Carcinoma) who haven't had treatment before. Participants should be fit enough for the treatments and not have any health conditions that could interfere with the study or their safety.

Inclusion Criteria

Women must not be breastfeeding while taking the study drug and for up to five months after the last dose of study drug

Willing and able to provide a signed and dated written informed consent

My kidney cancer includes clear cells.

Exclusion Criteria

I have or had cancer spread to my brain or spinal cord.

Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the investigator to unacceptably increase the risk of study participation

I haven't taken steroids or immunosuppressants in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Nivolumab + Ipilimumab or Nivolumab + Relatlimab + Ipilimumab on an outpatient basis

12 months

Every 3-4 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Relatlimab

Trial Overview The study compares two approaches: one group receives a combination of Nivolumab, Relatlimab, and Ipilimumab (triplet), while another gets just Nivolumab and Ipilimumab (doublet). The drugs are given intravenously on different schedules to see which works better against kidney cancer.

Participant Groups

Group I: Treatment with Nivolumab + Relatlimab + Ipilimumab Experimental Treatment 2 Interventions

Participants will randonmized to study and treatment will be administered on an outpatient basis.

Group II: Treatment with Nivolumab + Ipilimumab Experimental Treatment 2 Interventions

Participants will randonmized to study and treatment will be administered on an outpatient basis.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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 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 3 trial involving 1096 patients with untreated advanced renal-cell carcinoma, nivolumab plus ipilimumab significantly improved overall survival rates (75% at 18 months) compared to sunitinib (60% at 18 months), indicating a more effective treatment option for patients with intermediate or poor prognostic risk.

The objective response rate was also higher with nivolumab plus ipilimumab (42%) compared to sunitinib (27%), although both treatments had a high incidence of treatment-related adverse events, with nivolumab plus ipilimumab showing a slightly lower rate of severe (grade 3 or 4) events (46% vs. 63%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. Motzer, RJ., Tannir, NM., McDermott, DF., et al.[2022]

Nivolumab (Opdivo®) has been established as an effective second-line treatment for metastatic renal cell carcinoma (mRCC), showing improved overall survival (26 months vs. 19.7 months) and response rates compared to Everolimus, based on the CheckMate 025 trial with 1,080 participants.

The combination of Nivolumab and Ipilimumab has demonstrated a significantly higher objective response rate (42% vs. 27%) and better overall survival in intermediate and high-risk patients compared to Sunitinib, while also improving quality of life, despite an increase in immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for renal cell carcinoma - current status]. Grimm, MO., Foller, S.[2019]

In a study of 129 advanced renal cell carcinoma patients treated with nivolumab and ipilimumab, the occurrence of immune-related adverse events (irAEs) was linked to improved overall survival (OS) and progression-free survival (PFS), with significant hazard ratios indicating a strong positive association.

Patients who experienced multiple irAEs had even better survival outcomes, suggesting that the presence of these adverse events may be a marker for a more favorable response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis. Washino, S., Shirotake, S., Takeshita, H., et al.[2023]

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

The PRISM study is investigating whether administering ipilimumab every 12 weeks instead of every 3 weeks, when combined with nivolumab, can reduce severe side effects in patients with metastatic renal cell carcinoma (mRCC) without affecting treatment effectiveness.

This phase II trial aims to recruit 189 participants and will primarily measure the rate of grade 3 or 4 adverse reactions over 12 months, while also assessing progression-free survival and other important health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma. Buckley, HL., Collinson, FJ., Ainsworth, G., et al.[2022]

In a study of 46 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, 72% experienced immune-related adverse events (irAEs), which were linked to significantly longer progression-free survival (PFS) compared to those without irAEs.

While irAE development was an independent predictor of longer PFS, it did not affect overall survival (OS), suggesting that irAEs could serve as a useful prognostic marker for treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Ikeda, T., Ishihara, H., Nemoto, Y., et al.[2022]

In a study of 45 Japanese patients with untreated metastatic renal cell carcinoma, the combination therapy of nivolumab and ipilimumab showed a 41.5% objective response rate and a median progression-free survival of 17.8 months over a 2-year follow-up period.

The 2-year analysis indicated that nivolumab plus ipilimumab therapy's effectiveness aligns with previous studies, and second-line therapy following this combination also demonstrated a 20% objective response rate with a median progression-free survival of 9.8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study). Kojima, T., Kato, R., Sazuka, T., et al.[2022]

Nivolumab, when combined with ipilimumab, significantly improves overall survival rates in previously untreated advanced renal cell carcinoma (RCC), achieving an 18-month survival rate of 75% compared to 60% with sunitinib alone.

The combination therapy also results in a higher objective response rate of 42% versus 27% for sunitinib, indicating that immune checkpoint inhibitors are becoming a promising first-line treatment option for metastatic RCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frontline immunotherapy treatment with nivolumab and ipilimumab in metastatic renal cell cancer: a new standard of care. Nizam, A., Aragon-Ching, JB.[2020]

In a study of 18 patients with non-clear cell renal cell carcinoma (nccRCC) treated with ipilimumab plus nivolumab, 33.3% achieved partial responses, indicating that this combination therapy can be effective for this type of cancer.

However, the treatment was associated with significant toxicity, with 61.1% of patients experiencing treatment-related adverse events, including serious conditions like colitis and hepatotoxicity, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma. Gupta, R., Ornstein, MC., Li, H., et al.[2021]

References

1. 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]

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

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. [2022]

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

Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma. [2019]

4. France pubmed.ncbi.nlm.nih.gov

A Multi-institutional, Retrospective Analysis of Patients with Metastatic Renal Cell Carcinoma to Bone Treated with Combination Ipilimumab and Nivolumab. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

[Immunotherapy for renal cell carcinoma - current status]. [2019]

6. Japan pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis. [2023]

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

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

8. England pubmed.ncbi.nlm.nih.gov

PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma. [2022]

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

Safety and Efficacy of Nivolumab in Combination With Ipilimumab in Metastatic Renal Cell Carcinoma: The CheckMate 016 Study. [2022]

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

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study). [2022]

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

Frontline immunotherapy treatment with nivolumab and ipilimumab in metastatic renal cell cancer: a new standard of care. [2020]

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

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma. [2021]