Opdualag Received FDA Approval for Unresectable or Stage 4 Melanoma

For the first-line systemic treatment of unresectable or metastatic (stage 4) malignant melanoma in adult and pediatric patients aged 12 and older, nivolumab and relatlimab-rmbw in combination (Opdualag, Bristol-Myers Squibb Company) received FDA (US Food and Drug Administration) approval on March 18, 2022. Opdualag is a fixed-dose combination of the LAG-3-blocking antibody relatlimab and the programmed death receptor-1-blocking antibody nivolumab.

How Does Opdualag Work?

LAG-3 and PD-1 are two different immune checkpoints that deactivate the immune system's  T cells. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, had been shown to be safe and to have antitumor activity in previously treated melanoma patients. However, the phase II/III RELATIVITY-047 study was conducted to investigate its efficacy in previously untreated melanoma.

Below,  the mechanism of action of relatlimab and nivolumab is illustrated simply:

Details of the RELATIVITY-047 Study That Led to FDA Approval of Opdualag

Between May 2018 and December 2020, this double-blind clinical trial randomly assigned 714 patients from regions in North America, Central America, South America, Europe, Australia and New Zealand to receive relatlimab/nivolumab (355 patients) or nivolumab alone (359 patients).

Treatment consisted of 160 mg relatlimab plus 480 mg nivolumab, or 480 nivolumab alone, every 4 weeks until disease progression or unacceptable side effects.

Stratification factors were:

• LAG-3 expression status (≥ 1% or < 1% of positively staining immune cells) and
• PD-L1 expression status (≥ 1% or < 1% of tumor cells).

The study's primary endpoint was progression-free survival assessed by blinded independent central review.

Results

• At the analysis as of March 2021, median follow-up was 13.2 months.
• Median progression-free survival was 10.1 months in the relatlimab/nivolumab group (95% confidence interval [GA] = 6.4–15.7 months), compared with 4.6 months in the nivolumab group (95% GA = 3.4–5.6 months) (hazard ratio [HR] = 0.75, 95% GA = 0.62–0.92,  P  = 0.006).
• At month 12, PFS rates were 47.7% (95% GA = 41.8%-53.2%) and 36.0% (95% GA = 30.5%-41.6%).
• Combination therapy showed better progression-free survival regardless of tumor burden, LDH level and other prognostic factors.

Opdualag Side Effects

• Serious (grade 3 or 4) side effects occurred in 40.3% of the relatlimab/nivolumab group and 33.4% of the nivolumab group, and were considered treatment-related in 18.9% versus 9.7%.
• The most common treatment-related side effects of any grade in the relatlimab/nivolumab group were itching (23.4% versus 15.9%), fatigue (23.1% versus 12.8%) and rash (15.5% versus 12.0%); the most common grade 3 or 4 side effect was fatigue (1.1% versus 0.3%).
• Infusion-related reactions occurred in 5.9% versus 3.6% of patients.
• The most common immune-mediated side effects of any grade in the relatlimab/nivolumab group were hypothyroidism or thyroiditis (18.0% versus 13.9%), rash (9.3% versus 6.7%) and diarrhea/colitis (6.8% versus 3.1%); the most common grade 3 or 4 events were hepatitis (3.9% versus 1.1%) and adrenal insufficiency (1.4% versus 0%).

Opdualag Dose

For adult and pediatric patients aged 12 and older weighing at least 40 kg, the recommended Opdualag dose is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity. A recommended dose has not been established for pediatric patients aged 12 and older weighing less than 40 kg.