Nivolumab + Relatlimab for Melanoma Brain Metastases

Overseen By Hussein Tawbi, MD,PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: Autoimmune disease, Hepatitis, HIV, 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: 1

Duration: 100 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of drugs, nivolumab (Opdivo) and relatlimab (Opdualag), can manage melanoma that has spread to the brain. Researchers will study the safety and side effects of these drugs when used together. This trial suits individuals with melanoma and untreated brain metastases who are not currently experiencing symptoms from these brain lesions. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take certain medications like corticosteroids or other immunosuppressive drugs within 14 days before starting the study, unless they are for physiological replacement. It's best to discuss your specific medications with the study team.

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

Research shows that combining nivolumab and relatlimab is generally safe for patients with melanoma that has spread to the brain. In earlier studies, patients receiving this combination developed fewer new brain tumors compared to those receiving only nivolumab. This suggests the combination is effective without adding significant safety risks. Additionally, the one-year survival rate for patients was encouraging.

Some side effects have been reported, which is common with such treatments, but they were generally manageable. Importantly, this combination is being tested at a stage where treatments have already shown some evidence of safety in humans. This trial will help further confirm its safety and effectiveness for treating brain tumors in melanoma. ^{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 melanoma brain metastases because it offers a novel approach compared to existing treatments. Unlike traditional treatments that often focus on surgery or radiation, this combination leverages the immune system to fight cancer. Nivolumab is an immune checkpoint inhibitor that blocks the PD-1 protein on T cells, boosting the immune response against cancer cells. Relatlimab targets another checkpoint, LAG-3, which can further enhance the immune attack on tumors. This dual mechanism has the potential to provide a more effective treatment option by overcoming the limitations of current therapies.

What evidence suggests that this treatment might be an effective treatment for melanoma brain metastases?

Research has shown that using nivolumab and relatlimab together may help treat melanoma, a type of skin cancer. Studies have found that this combination can slow the disease in patients with advanced melanoma. Notably, half of the patients using this combination went twice as long without their cancer worsening compared to those on standard treatments. In this trial, participants will receive the combination of nivolumab and relatlimab to evaluate its effectiveness specifically for melanoma that has spread to the brain. While specific data on its effectiveness for brain metastases is not yet available, experts believe it could be beneficial. Early results suggest that using nivolumab and relatlimab together is more effective than using nivolumab alone, especially for certain patients. ^{3 6 7 8 9}

Who Is on the Research Team?

Hussein A. Tawbi

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with melanoma that has spread to the brain. Participants must have a measurable brain tumor, be able to follow the study plan, and not have had certain previous treatments like checkpoint inhibitors in the metastatic setting or whole-brain radiation. They should not need steroids, be pregnant or breastfeeding, and must use birth control if applicable.

Inclusion Criteria

I had surgery and radiation for up to 5 brain metastases and fully recovered without any lasting brain issues.

I am not pregnant, not breastfeeding, and will use birth control during and after the study.

My side effects from previous cancer treatments are mild or gone, except for stable hormone issues.

Exclusion Criteria

I had cancer before, but it's been treated and I've been cancer-free for over 2 years.

I have a wound, ulcer, or bone fracture that hasn’t healed.

You have been diagnosed with HIV, the virus that causes AIDS.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab in combination with relatlimab by vein over about 30 minutes on Day 1 of each 28-day study cycle, for up to 25 cycles

100 weeks

1 visit per 28-day cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Relatlimab

Trial Overview

The trial tests combining Nivolumab with Relatlimab against active melanoma brain metastases. It aims to see if this drug combination can control cancer growth in the brain and will also monitor safety and side effects of these drugs when used together.

How Is the Trial Designed?

Group I: Relatlimab+Nivolumab Experimental Treatment 3 Interventions

Participants will receive nivolumab in combination with relatlimab by vein over about 30 minutes on Day 1 of each 28-day study cycle. You may receive up to 25 doses of the study drugs.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Recent phase 2 clinical trials have shown that immune checkpoint inhibitors can lead to durable responses in patients with brain metastases, particularly in melanoma, improving median survival beyond the historical average of months.

However, these therapies can also increase the risk of neurologic toxicities, such as symptomatic edema and radiation necrosis, highlighting the need for careful management and a multidisciplinary approach in treating these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications associated with immunotherapy for brain metastases. Tran, TT., Jilaveanu, LB., Omuro, A., et al.[2023]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

In a phase 2 study involving 94 patients with untreated brain metastases from melanoma, the combination of nivolumab and ipilimumab demonstrated a significant intracranial clinical benefit rate of 57%, indicating effective treatment for brain metastases.

The treatment was associated with a safety profile similar to that of patients without brain metastases, although 55% of patients experienced grade 3 or 4 adverse events, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. Tawbi, HA., Forsyth, PA., Algazi, A., et al.[2022]

Nivolumab demonstrated efficacy in patients with non-squamous non-small-cell lung cancer (NSCLC) and brain metastases, achieving a disease control rate of 39% and a median overall survival of 8.6 months, despite the poor prognosis typically associated with this condition.

The safety profile of nivolumab in this expanded access program was consistent with previous studies, with only 7% of patients discontinuing treatment due to adverse events, indicating it is a tolerable option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Crinò, L., Bronte, G., Bidoli, P., et al.[2019]

Pembrolizumab, an anti-PD-1 antibody, has shown a rapid and sustained response in a patient with symptomatic brain metastases from melanoma, achieving complete remission for over a year without the need for additional radiotherapy.

This case suggests that pembrolizumab may be effective for treating brain metastases in melanoma patients, highlighting the importance of conducting further clinical studies to explore its potential in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid remission of symptomatic brain metastases in melanoma by programmed-death-receptor-1 inhibition. Lüttmann, N., Grätz, V., Haase, O., et al.[2018]

Metastatic melanoma often spreads to the brain, leading to poor outcomes, and traditional treatments like chemotherapy have limited effectiveness for brain metastases.

Recent advancements, particularly with the anti-CTLA-4 antibody ipilimumab and BRAF inhibitors (dabrafenib and vemurafenib), show promising initial efficacy in treating active brain metastases, suggesting a shift towards more effective combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint blockade in patients with melanoma metastatic to the brain. Di Giacomo, AM., Margolin, K.[2021]

In a phase 2 trial involving 36 patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC), pembrolizumab demonstrated activity, achieving a brain metastasis response in 22% of melanoma patients and 33% of NSCLC patients, with responses being durable for most.

The treatment had an acceptable safety profile, with serious adverse events occurring in a small percentage of patients, indicating that systemic immunotherapy could be a viable option for those with untreated or progressive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Goldberg, SB., Gettinger, SN., Mahajan, A., et al.[2022]

In a study of 2,753 patients with stage 4 melanoma, those with melanoma brain metastases (MBMs) experienced a significant increase in 4-year overall survival (OS) from 7.4% to 14.1% following the approval of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapies.

Patients with MBMs who received CBI showed improved median OS of 12.4 months and a 4-year OS of 28.1%, especially benefiting those without extracranial metastases, who had a median OS of 56.4 months and a 4-year OS of 51.5%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Risk-Adjusted Survival for Melanoma Brain Metastases in the Era of Checkpoint Blockade Immunotherapies: Results from a National Cohort. Iorgulescu, JB., Harary, M., Zogg, CK., et al.[2022]

In a study of 129 patients with advanced melanoma treated with nivolumab and relatlimab, those without diabetes had significantly better progression-free survival (PFS) and overall survival (OS) compared to patients with type 2 diabetes, indicating that diabetes negatively impacts treatment efficacy.

Interestingly, patients who developed immune checkpoint inhibitor-induced diabetes (ICI-DM) during treatment had the best outcomes, suggesting that this condition may enhance the effectiveness of the therapy, possibly due to changes in LAG3 expression in tumor tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. Mallardo, D., Woodford, R., Menzies, AM., et al.[2023]

Nivolumab and ipilimumab show significant intracranial activity in patients with melanoma brain metastases, with response rates of 46% and 57% in two phase II studies, respectively.

Nivolumab can penetrate the cerebrospinal fluid (CSF), achieving concentrations that are effective for therapeutic action, challenging the belief that large molecules like monoclonal antibodies cannot affect the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial antitumor responses of nivolumab and ipilimumab: a pharmacodynamic and pharmacokinetic perspective, a scoping systematic review. van Bussel, MTJ., Beijnen, JH., Brandsma, D.[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]

In a study of 119 patients with melanoma brain metastases, those who were asymptomatic showed a significant clinical benefit from the combination of nivolumab and ipilimumab, with a 36-month overall survival rate of 71.9%.

Symptomatic patients had much lower efficacy, with only 36.6% overall survival at 36 months, highlighting the challenges in treating symptomatic melanoma brain metastases with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Tawbi, HA., Forsyth, PA., Hodi, FS., et al.[2022]

In a study of 380 patients with melanoma brain metastasis (MBM), treatment with nivolumab plus ipilimumab, especially when combined with local therapies like stereotactic radiosurgery or surgery, significantly improved overall survival (OS) rates, with 2-year and 3-year OS rates at 41% and 30%, respectively.

The study found that the timing of immunotherapy (first-line or later) did not affect OS, and factors such as elevated serum lactate dehydrogenase levels and the number of brain metastases were significant prognostic indicators for survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients. Amaral, T., Kiecker, F., Schaefer, S., et al.[2021]

In asymptomatic patients with melanoma brain metastases (MBM), nivolumab plus ipilimumab showed a high intracranial clinical benefit rate of 58.4% and provided durable responses, suggesting it is an effective first-line treatment option.

For symptomatic patients requiring corticosteroids, the treatment had a much lower intracranial clinical benefit rate of 22.2%, indicating limited efficacy and highlighting the need for alternative therapies for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204). Tawbi, HA., Forsyth, PA., Hodi, FS., et al.[2021]

Citations

1.

ncbi.nlm.nih.gov

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

Clinical Review - Nivolumab and Relatlimab (Opdualag) - NCBI

The experts also stated that it will be important to follow OS data as they mature, to determine the efficacy in brain metastases, and whether the combination ...

2.

cancernetwork.com

cancernetwork.com/view/nivolumab-relatlimab-elicit-ic-activity-in-anti-pd-l1-refractory-melanoma-brain-mets

Nivolumab/Relatlimab Elicit IC Activity in Anti–PD-L1– ...

The combination elicited a clinical benefit rate of 63.0% and an overall response rate of 22.2% in anti–PD-L1–refractory melanoma with melanoma ...

3.

opdualag.com

opdualag.com/about/results

Advanced Melanoma Clinical Trial Results

Half the patients on Opdualag went 2X longer without advanced melanoma worsening than those on a standard treatment. In a clinical trial of 714 patients ...

4.

targetedonc.com

targetedonc.com/view/tawbi-discusses-the-role-of-brain-metastases-and-pd-l1-status-in-melanoma

Tawbi Discusses the Role of Brain Metastases and PD-L1 ...

Both nivolumab combination therapies are more effective than single-agent nivolumab and additional benefit was shown in patients with PD-L1–positive disease.

5.

sciencedirect.com

sciencedirect.com/science/article/pii/S2772611825000060

Selecting first-line immunotherapy in advanced melanoma

Currently there are no data on the activity of nivolumab-relatlimab in patients with brain metastases; a phase 2 study is ongoing (NCT05704647). 6. Acral ...

6.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e14001

Real-world outcomes in patients with brain metastases ...

Real-world outcomes in patients with brain metastases secondary to melanoma treated with nivolumab/relatlimab. Authors: Erika Yamazawa, Justine ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11795373/

Real-world outcomes in patients with melanoma brain ...

In that trial, new CNS metastases developed less frequently in patients treated with nivolumab plus relatlimab than with nivolumab alone (5% vs ...

8.

nature.com

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

Adjuvant nivolumab and relatlimab in stage III/IV melanoma

The secondary endpoint of distant metastasis-free survival (DMFS) showed a hazard ratio for nivolumab plus relatlimab versus nivolumab of 1.07 ( ...

9.

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 ...