In the phase II/III RELATIVITY-047 trial reported in The New England Journal of Medicine, Hussein A. Tawbi, MD, PhD, and colleagues found that the addition of relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, to nivolumab, a PD-1 inhibitor, significantly prolonged progression-free survival in patients with previously untreated metastatic or unresectable melanoma.
As stated by the investigators, “LAG-3 and PD-1 are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3–blocking antibody, and nivolumab, a PD-1–blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.”
Hussein A. Tawbi, MD, PhD
Study Details
In the double-blind trial, 714 patients from sites in North America, Central America, South America, Europe, Australia, and New Zealand were randomly assigned between May 2018 and December 2020 to receive relatlimab/nivolumab (n = 355) or nivolumab alone (n = 359). Treatment consisted of a fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg or nivolumab ay 480 mg every 4 weeks until disease progression or unacceptable toxicity.
Stratification factors included LAG-3 expression status (≥ 1% or < 1% of immune cells with positive staining) and PD-L1 expression status (≥ 1% or < 1% of tumor cells). A total of 8.1% of patients had M0 disease.
The primary endpoint was progression-free survival on blinded independent central review.
Progression-Free Survival
At database lock (March 2021), median follow-up was 13.2 months. Median progression-free survival was 10.1 months (95% confidence interval [CI] = 6.4–15.7 months) in the relatlimab/nivolumab group vs 4.6 months (95% CI = 3.4–5.6 months) in the nivolumab group (hazard ratio [HR] = 0.75, 95% CI = 0.62–0.92, P = .006). Rates at 12 months were 47.7% (95% CI = 41.8%–53.2%) vs 36.0% (95% CI = 30.5%–41.6%).
According to PD-L1 expression status, median progression-free survival was 15.7 months vs 14.7 months (HR = 0.95, 95% CI = 0.68–1.33) among 146 vs 147 patients with PD-L1 ≥ 1% and 6.4 months vs 2.9 months (HR = 0.66, 95% CI = 0.51–0.84) among 209 vs 212 with PD-L1 < 1%.
According to LAG-3 expression status, median progression-free survival was 12.6 vs 4.8 months (HR = 0.75, 95% CI = 0.59–0.95) among 268 vs 269 patients with LAG-3 ≥ 1% and 4.8 vs 2.8 months (HR = 0.78, 95% CI = 0.54–1.15) among 87 vs 90 patients with LAG-3 < 1%.
According to BRAF status, median progression-free survival was 10.1 vs 4.6 months (HR = 0.74, 95% CI = 0.54–1.03) among 136 vs 139 patients with a BRAF mutation and 10.1 vs 4.6 months (HR = 0.76, 95% CI = 0.59–0.98) among 219 vs 220 without a BRAF mutation.
KEY POINTS
- Relatlimab/nivolumab significantly improved progression-free survival vs nivolumab alone.
- Median progression-free survival was 10.1 vs 4.6 months, with 1-year rates of 48% vs 36%.
Adverse Events
Grade 3 or 4 adverse events occurred in 40.3% of those in the relatlimab/nivolumab group vs 33.4% of the nivolumab group and were considered treatment-related in 18.9% vs 9.7%. The most common treatment-related adverse events of any grade in the relatlimab/nivolumab group were pruritus (23.4% vs 15.9% in nivolumab group), fatigue (23.1% vs 12.8%), and rash (15.5% vs 12.0%); the most common grade 3 or 4 adverse event was fatigue (1.1% vs 0.3%).
Infusion-related reactions occurred in 5.9% vs 3.6% of patients. The most common immune-mediated adverse events of any grade in the relatlimab/nivolumab group were hypothyroidism or thyroiditis (18.0% vs 13.9%), rash (9.3% vs 6.7%), and diarrhea/colitis (6.8% vs 3.1%); the most common grade 3 or 4 events were hepatitis (3.9% vs 1.1%) and adrenal insufficiency (1.4% vs 0%).
The investigators concluded, “The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals.”
Disclosure: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit nejm.org.
