Education and decision-support only — not a medical device or personalised advice. Always discuss your specific situation with your specialist team.
If you have been diagnosed with Stage III or Stage IV (advanced) melanoma that cannot be surgically removed, your oncologist may mention nivolumab plus relatlimab — marketed as Opdualag. This article explains what the combination is, what the clinical trial evidence shows, who it may be suitable for, and what to expect.
What is Opdualag?
Opdualag is a fixed-dose combination immunotherapy that contains two checkpoint inhibitors:
- Nivolumab — an anti-PD-1 antibody that has been used for melanoma since 2014. It blocks the PD-1 "brake" on immune T-cells, helping them recognise and attack melanoma cells.
- Relatlimab — an anti-LAG-3 antibody. LAG-3 is a different immune checkpoint (a second "brake") that cancer cells exploit. Blocking both PD-1 and LAG-3 simultaneously may produce a stronger anti-tumour response than blocking either alone.
Together, the two drugs are given as a single intravenous infusion once every four weeks.
Opdualag was approved by the FDA in March 2022 for adults and children aged 12 and older with unresectable or metastatic melanoma. It is listed in the ESMO 2023 Clinical Practice Guidelines as a first-line option for advanced melanoma.
What the RELATIVITY-047 trial showed
The evidence for Opdualag comes primarily from RELATIVITY-047, a large randomised Phase 3 trial that compared:
- Opdualag (nivolumab + relatlimab) vs
- Nivolumab alone
in 714 patients with previously untreated advanced (unresectable Stage III or Stage IV) melanoma [1].
Key results at first reporting (median follow-up 13 months):
| Outcome | Opdualag | Nivolumab alone |
|---|---|---|
| Progression-free survival (PFS) at 12 months | 47.7% | 36.0% |
| Median PFS | 10.1 months | 4.6 months |
| Hazard ratio for progression or death | 0.75 (95% CI 0.62–0.92) |
Put simply: patients receiving the combination were about 25% less likely to experience disease progression or death compared with patients receiving nivolumab alone at any given time point.
Three-year update (JCO 2025): At three years' follow-up, the overall survival (OS) benefit was maintained. Three-year OS was approximately 58% with Opdualag vs 52% with nivolumab — an absolute difference of around 6 percentage points [2].
These results established the combination as an evidence-based first-line option.
How does Opdualag compare to nivolumab + ipilimumab?
You may also have heard of nivolumab + ipilimumab (Opdivo + Yervoy, CheckMate 067 trial), which is another dual-checkpoint combination for advanced melanoma. A published indirect comparison using propensity-score weighting found that Opdualag's efficacy appeared broadly similar to nivo+ipi, but with a notably lower rate of high-grade (grade 3–4) immune-related side effects [3]:
- Grade 3–4 treatment-related adverse events: ~19% with Opdualag vs ~55% with nivo+ipi
This suggests Opdualag may offer comparable anti-tumour activity with a more manageable toxicity profile, though head-to-head randomised data do not yet exist.
Who may be eligible for Opdualag?
Opdualag is used in first-line treatment for:
- Unresectable Stage III melanoma (cannot be completely removed by surgery)
- Stage IV (metastatic) melanoma
- Cutaneous (skin) melanoma — the evidence base is predominantly for this type
It may NOT be the primary choice if:
- Your tumour tests positive for the BRAF V600 mutation and your oncologist prefers to start with targeted therapy (BRAF + MEK inhibitors), which can produce faster initial responses
- You have certain autoimmune conditions that increase the risk of immune-related side effects
Your oncologist will discuss your BRAF mutation status, overall health, and goals of care before recommending the right first-line option.
What side effects should I expect?
As a dual immunotherapy, Opdualag can cause immune-related adverse events (irAEs) — conditions where the immune system, now less inhibited, attacks normal tissues. Common effects include:
- Fatigue — very common
- Skin rash / itching (dermatitis) — common
- Thyroid problems (hypothyroidism or hyperthyroidism) — common; usually manageable with medication
- Colitis (gut inflammation, diarrhoea) — less common but important to report promptly
- Liver inflammation (elevated liver enzymes) — monitored by blood tests
- Pneumonitis (lung inflammation) — less common but serious
Most irAEs are reversible with corticosteroids if caught early. Your team will give you a list of symptoms to watch for and a 24-hour contact number. Report any new symptom promptly — early treatment prevents most irAEs from becoming serious.
Practical tips for patients
- Ask your oncologist about LAG-3 status: unlike PD-L1 or BRAF, LAG-3 expression is not routinely tested before prescribing Opdualag (the RELATIVITY-047 trial did not select by LAG-3 level). You do not need a biomarker test to be eligible.
- Ask about active clinical trials: new combinations building on LAG-3 blockade are in development. If you have not yet started first-line therapy, ask whether a trial is open at your centre.
- Bring a list of your medications: some drugs (especially other immunosuppressants) interact with checkpoint inhibitors.
See our Clinical Trial Finder and Patient resources for further support organisations.
References
[1] Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022;386(1):24–34. PMID 34986285A
[2] Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047. J Clin Oncol. 2025. PMID 39671533
[3] First-Line Nivolumab Plus Relatlimab Versus Nivolumab Plus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2024. PMID 39137386
Education and decision-support only — not a medical device. Does not diagnose, screen, predict, or provide personalised medical advice. Discuss all treatment decisions with your specialist team.