What is the role of Opdualag (nivolumab and relatlimab) in treating a patient with advanced or metastatic melanoma?

Opdualag (Nivolumab + Relatlimab) for Melanoma

Opdualag (nivolumab 480 mg + relatlimab 160 mg fixed-dose combination) is a reasonable first-line treatment option for unresectable or metastatic melanoma, offering improved progression-free survival over nivolumab monotherapy with a more favorable toxicity profile than nivolumab plus ipilimumab, though it has not yet demonstrated a statistically significant overall survival benefit. 1

Primary Treatment Indications

Unresectable or Metastatic Melanoma (First-Line)

For BRAF wild-type disease, nivolumab plus relatlimab is one of four reasonable first-line options alongside nivolumab plus ipilimumab, single-agent nivolumab, and single-agent pembrolizumab. 1

• The RELATIVITY-047 trial demonstrated median PFS of 10.2 months with nivolumab plus relatlimab versus 4.6 months with nivolumab alone (HR 0.75-0.78), representing approximately 5.5 months of additional disease control 1, 2
• The objective response rate was 43.1% with combination therapy versus 32.6% with nivolumab monotherapy, a 10.5 percentage-point improvement 2
• Median overall survival was not reached with the combination versus 34.1 months with nivolumab alone (HR 0.80), but this did not meet the prespecified statistical threshold for significance (p=0.059) 2

For BRAF-mutant disease, nivolumab plus relatlimab is one of seven reasonable first-line options, including targeted therapy combinations (dabrafenib plus trametinib, encorafenib plus binimetinib, vemurafenib plus cobimetinib). 1

Neoadjuvant Setting (Resectable Stage III/Oligometastatic Stage IV)

Nivolumab 480 mg plus relatlimab 160 mg every 4 weeks for 2 doses before surgery, followed by 10 adjuvant doses, is an NCCN Category 2A "other recommended regimen" for resectable stage IIIB-D or oligometastatic stage IV melanoma. 1

• The neoadjuvant regimen achieved a 57% pathologic complete response rate and 70% overall pathologic response rate in 30 patients 1, 3
• No grade 3-4 immune-related adverse events occurred during neoadjuvant treatment 1, 3
• Two-year recurrence-free survival was 92% for pathologic responders versus 55% for non-responders (p=0.005) 1, 3

Toxicity Profile and Safety Considerations

Grade 3-4 treatment-related adverse events occur in 18.9-21.1% of patients receiving nivolumab plus relatlimab, compared to 9.7-11.1% with nivolumab monotherapy but substantially lower than the 33-59% rate with nivolumab plus ipilimumab. 1, 2

• The most common adverse events include fatigue, which occurs in 16-37% of patients on anti-PD-1 therapy 1
• Immune-related adverse events typically manifest within the first 8-12 weeks of treatment, with skin toxicities often appearing first 1
• Monitor for colitis, hepatitis, pneumonitis, endocrinopathies, and dermatologic toxicities throughout treatment 4
• Patients have increased susceptibility to severe infections, particularly tuberculosis and bacterial infections, due to PD-1 blockade impairing normal immune responses 4

Treatment Administration and Duration

Administer nivolumab 480 mg plus relatlimab 160 mg intravenously every 4 weeks. 1, 2

• Treatment can be continued beyond 2 years if ongoing response is demonstrated 5
• For patients achieving complete response after ≥6 months of therapy, treatment discontinuation can be considered, with 85-90% remaining disease-free 5
• In the neoadjuvant setting, start treatment within 13 weeks of planned surgery 4

Clinical Decision-Making Algorithm

Choose nivolumab plus relatlimab when:

1. Patient has unresectable or metastatic melanoma requiring first-line systemic therapy
2. Patient desires combination immunotherapy for improved PFS over single-agent therapy
3. Patient cannot tolerate or wishes to avoid the higher toxicity of nivolumab plus ipilimumab
4. Patient has resectable stage III disease and is a candidate for neoadjuvant therapy with favorable toxicity profile

Avoid nivolumab plus relatlimab when:

1. Patient has brain metastases—nivolumab plus ipilimumab is preferred based on phase II trial data showing superior intracranial response 1
2. Patient prioritizes overall survival data over PFS, as OS benefit has not been definitively established 2
3. Patient has contraindications to immunotherapy and has BRAF V600E/K mutation—use dabrafenib plus trametinib instead 4

Common Pitfalls and Caveats

• Do not assume OS benefit: While PFS is improved, the combination has not yet demonstrated statistically significant overall survival benefit over nivolumab monotherapy, unlike nivolumab plus ipilimumab which has shown clear OS advantage 1, 2
• Recognize the trade-off: This regimen occupies a middle ground—better efficacy than single-agent therapy but less toxic than nivolumab plus ipilimumab, yet without the proven survival benefit of the latter 1
• Consider disease burden: Patients with rapidly progressive disease or high tumor burden may benefit more from the more aggressive nivolumab plus ipilimumab combination despite higher toxicity 1
• BRAF testing is mandatory: Always confirm BRAF mutation status before initiating therapy, as this determines the full range of treatment options including targeted therapy 5