Subcutaneous Nivolumab + Relatlimab for Melanoma

(RELATIVITY-127 Trial)

Not currently recruiting at 350 trial locations

Overseen By BMS Clinical Trials Contact Center www.BMSClinicalTrials.com

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Bristol-Myers Squibb

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Ocular melanoma, Myocarditis, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method of administering a combination of nivolumab and relatlimab to treat advanced melanoma, a serious type of skin cancer. Researchers aim to determine if subcutaneous injections of these drugs work as effectively as the traditional IV drip method. The trial targets individuals with melanoma that has spread or cannot be surgically removed. Ideal candidates are those with Stage III or IV melanoma who have not yet received treatment. As a Phase 3 trial, this study represents the final step before FDA approval, allowing participants to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that participants do not take systemic corticosteroids or other immunosuppressive medications within 14 days before starting the study treatment. Inhaled or topical steroids are allowed if you don't have an active autoimmune disease.

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic corticosteroids or other immunosuppressive medications at least 14 days before starting the study treatment. However, inhaled or topical steroids and certain adrenal replacement doses are allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of nivolumab and relatlimab is generally well-tolerated in patients with melanoma. Studies have found that this treatment can significantly shrink tumors and help patients live longer without their cancer worsening. Importantly, the safety profile of this combination aligns with what is known about each drug individually, indicating no new safety concerns.

In the reviewed studies, reported side effects were similar to those seen with other treatments of this type. These include tiredness and skin reactions, while serious side effects were less common. The combination's testing in a late-stage trial suggests that earlier research deemed it safe enough for further evaluation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for melanoma?

Researchers are excited about the combination of Nivolumab and Relatlimab for treating melanoma because it introduces a new way to target the immune system. Unlike standard treatments that primarily focus on either CTLA-4 or PD-1 pathways, this fixed-dose combination tackles both PD-1 and LAG-3, offering a dual mechanism that could enhance the immune response against cancer cells. Additionally, the treatment is available in a subcutaneous form, which could make administration more convenient compared to the traditional intravenous methods, potentially improving patient comfort and compliance.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research shows that using nivolumab and relatlimab together effectively treats melanoma. One study found that this combination significantly increased the time patients lived without their disease worsening. Additionally, a three-year analysis showed that patients lived longer overall with these drugs. In this trial, participants will receive either the subcutaneous (SC) or intravenous (IV) fixed-dose combination of nivolumab and relatlimab. Previous studies have shown that this combination works better than using nivolumab alone. These results strongly support the treatment's effectiveness for managing melanoma that cannot be surgically removed or has spread to other parts of the body. ^{2 3 6 7 8}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for people aged 12 and older with Stage III (unresectable) or Stage IV (metastatic) melanoma, as per AJCC staging. They must have measurable disease by CT or MRI, be in good physical condition (ECOG ≤1), and adolescents must weigh at least 40 kg. It's not for those with ocular melanoma, a history of myocarditis, or on high-dose steroids/immunosuppressants.

Inclusion Criteria

My melanoma is at Stage III (unresectable) or IV (metastatic).

I am very active or have minor symptoms that don't limit my daily activities.

My melanoma is at Stage III (unresectable) or Stage IV (metastatic).

Exclusion Criteria

I do not have eye melanoma.

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

I have never had myocarditis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either subcutaneous or intravenous administration of nivolumab + relatlimab FDC

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab + Relatlimab Fixed-dose Combination (FDC)

Trial Overview The study tests if the subcutaneous form of Nivolumab + Relatlimab combination is as effective as the intravenous version in untreated metastatic/unresectable melanoma patients. The focus is on comparing drug exposure levels between these two methods.

How Is the Trial Designed?

Group I: Nivolumab + Relatlimab FDC SC Experimental Treatment 2 Interventions

Group II: Nivolumab + Relatlimab FDC IV Active Control 1 Intervention

Nivolumab + Relatlimab Fixed-dose Combination (FDC) is already approved in United States for the following indications:

Approved in United States as Opdualag for:

• Advanced melanoma (unresectable or metastatic)

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead 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

Published Research Related to This Trial

Combining ipilimumab with nivolumab can significantly improve treatment outcomes for advanced melanoma patients, but ipilimumab alone is not effective for those resistant to nivolumab.

A case study demonstrated that a nivolumab-resistant patient with multiple in-transit melanomas responded well to a combination of ipilimumab and topical imiquimod, suggesting a potential new treatment strategy for similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod. Fujimura, T., Kambayashi, Y., Sato, Y., et al.[2020]

Nivolumab plus relatlimab is a combination immunotherapy that targets immune checkpoints, specifically PD-1 and LAG-3, and has been approved for treating unresectable or metastatic melanoma in adults and adolescents weighing at least 40 kg.

This combination therapy represents a significant advancement in cancer treatment, as it utilizes two different mechanisms to enhance the immune response against cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab: First Approval. Paik, J.[2022]

Nivolumab (Opdivo) monotherapy led to complete regression of local recurrence and multiple lung metastases in a patient with recurrent skin melanoma and a positive BRAF mutation, demonstrating its efficacy as a treatment option.

After 5 courses of nivolumab, the patient experienced significant improvement in her condition, achieving an ECOG performance status of 0, indicating a return to an active lifestyle without pain, and normal serum LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. Samsonia, M., Kandelaki, M., Gibradze, O., et al.[2021]

Nivolumab, either alone or in combination with ipilimumab, significantly improves response rates in patients with advanced unresectable melanoma compared to ipilimumab alone, with a relative risk of 3.58 for objective response rates and 5.93 for complete response rates based on a review of four randomized-controlled trials involving 1910 patients.

Nivolumab also offers longer progression-free survival compared to ipilimumab alone, while maintaining a comparable safety profile, indicating its efficacy as a first-line treatment option for advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab monotherapy or in combination with ipilimumab for metastatic melanoma: systematic review and meta-analysis of randomized-controlled trials. Menshawy, A., Eltonob, AA., Barkat, SA., et al.[2023]

In the RELATIVITY-047 trial, the combination of nivolumab and relatlimab (NIVO + RELA) significantly improved progression-free survival in patients with advanced melanoma compared to nivolumab alone, with a median follow-up of 19.3 months.

Despite a higher incidence of severe treatment-related adverse events with the combination therapy, patients reported stable health-related quality of life, indicating that the benefits of NIVO + RELA outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with nivolumab plus relatlimab versus nivolumab monotherapy in patients with previously untreated unresectable or metastatic melanoma: RELATIVITY-047 trial. Schadendorf, D., Tawbi, H., Lipson, EJ., et al.[2023]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

The combination of ipilimumab and nivolumab is more effective in treating advanced melanoma compared to ipilimumab alone, leading to better patient responses.

However, this two-drug combination significantly increases the likelihood of side effects compared to using ipilimumab as a single treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab + ipilimumab ups melanoma response. [2018]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

The combination of nivolumab and ipilimumab, two immune checkpoint inhibitors, is a promising treatment for advanced melanoma, enhancing the body's immune response against the cancer.

Adding denosumab to this treatment may further improve anti-tumor effects by counteracting the immunosuppressive environment created by CD8+ T cells, as suggested by recent reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. Yoshida, S., Fujimura, T., Kambayashi, Y., et al.[2020]

Citations

1. opdualaghcp.com opdualaghcp.com/efficacy/melanoma/relativity-047

Efficacy | Opdualag® (nivolumab and relatlimab-rmbw) for HCPs View efficacy data for Opdualag (nivolumab and relatlimab-rmbw) in unresectable or metastatic melanoma. Please see Indications and Important Safety ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.01124

Three-Year Overall Survival With Nivolumab Plus ... Nivolumab plus relatlimab demonstrated a statistically significant improvement in progression-free survival (PFS), along with a clinically meaningful, but not ...

3. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK604840/

Clinical Review - Nivolumab and Relatlimab (Opdualag) - NCBI The response rates of combination ipilimumab-nivolumab is approximately 56%. Patients may initially respond and eventually progress. After progression, new ...

4. nature.com nature.com/articles/s41591-025-04032-8

Adjuvant nivolumab and relatlimab in stage III/IV melanoma However, approximately 50% of patients have disease recurrence, with 5-year RFS rates of 50% for nivolumab, 55% for pembrolizumab and 52% for ...

5. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2200239

Overall Survival and Response with Nivolumab and ... The fixed-dose combination of nivolumab + relatlimab showed consistent PFS benefit versus nivolumab with approximately 6 months of additional median follow-up.

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2109970

Relatlimab and Nivolumab versus Nivolumab in Untreated ... The combination of relatlimab and nivolumab, a PD-1 inhibitor, showed antitumor activity, including durable objective responses in patients with melanoma that ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05625399

NCT05625399 | A Study of Subcutaneous Nivolumab + ... The purpose of this study is to demonstrate that the study drug exposure level of the nivolumab + relatlimab FDC subcutaneous (SC) formulation is not worse ...

8. news.bms.com news.bms.com/news/details/2025/Bristol-Myers-Squibb-Provides-Update-on-Phase-3-RELATIVITY-098-Trial/default.aspx

Bristol Myers Squibb Provides Update on Phase 3 ... The safety profile of Opdualag observed in this analysis was consistent with the known profiles of nivolumab and relatlimab. “We are ...