In a phase II/III trial (RELATIVITY-047) reported in The New England Journal of Medicine, Hussein A. Tawbi, MD, PhD, of The University of Texas MD Anderson Cancer Center, and colleagues found that the addition of relatlimab, a lymphocyte-activation gene 3 (LAG-3)–blocking antibody, to nivolumab significantly prolonged progression-free survival in patients with previously untreated metastatic or unresectable melanoma.¹

Hussein A. Tawbi, MD, PhD

The investigators stated: “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.”

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 alone at 480 mg, every 4 weeks, until disease progression or unacceptable toxicity. Randomization was stratified by LAG-3 expression status (≥ 1% or < 1% of immune cells with positive staining), PD-L1 expression status (≥ 1% or < 1% of tumor cells), BRAF mutation status, and metastasis stage (M0, M1, and normal lactate dehydrogenase [LDH] levels vs M1 with elevated LDH levels). The primary endpoint was progression-free survival on blinded independent central review.

For the relatlimab/nivolumab vs nivolumab-alone groups, median age was 63 years (range = 20–94 years) vs 62 years (range = 21–90 years), 40.8% vs 42.6% were female, and 8.7% vs 7.2% had received prior adjuvant systemic therapy. Metastasis stage was M0 in 9.9% vs 6.4%, M1a/b in 45.6% vs 54.3%, M1c in 42.5% vs 35.4%, and M1d in 1.7% vs 3.1%. Melanoma subtype was cutaneous nonacral in 70.1% vs 70.8%. Eastern Cooperative Oncology Group performance status was 0 (66.5% vs 67.4%) or 1 in all patients. LDH levels were above the upper limit of normal in 36.6% vs 35.7% and more than twice the upper limit of normal in 9.0% vs 8.6%. LAG-3 expression was at least 1% in 75.5% vs 74.9% and less than 1% in 24.5% vs 25.1%. PD-L1 expression was at least 1% in 41.1% vs 40.9% and less than 1% in 58.9% vs 59.1%, and 38.3% vs 38.7% had BRAF mutation and 61.7% vs 61.3% did not. Overall, 65.4% vs 66.0% had M0, M1, and normal LDH levels and 34.6% vs 34.0% had M1 and elevated LDH levels.

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%).

In stratification subgroups, median progression-free survival was 15.7 months vs 14.7 months (HR = 0.95, 95% CI = 0.68–1.33) among patients with PD-L1 ≥ 1% and 6.4 months vs 2.9 months (HR = 0.66, 95% CI = 0.51–0.84) among those with PD-L1 < 1%; 12.6 vs 4.8 months (HR = 0.75, 95% CI = 0.59–0.95) among patients with LAG-3 ≥ 1% and 4.8 vs 2.8 months (HR = 0.78, 95% CI = 0.54–1.15) among those with LAG-3 < 1%; and 10.1 vs 4.6 months (HR = 0.74, 95% CI = 0.54–1.03) among patients with BRAF mutation and 10.1 vs 4.6 months (HR = 0.76, 95% CI = 0.59–0.98) among those without BRAF mutation. Hazard ratios were 0.71 (95% CI = 0.55–0.92) among patients with M0, M1, and normal LDH levels and 0.79 (95% CI = 0.58–1.09) among those with M1 and elevated LDH levels.

At the time of the primary analysis of progression-free survival, a prespecified interim analysis of overall survival did not reach significance. Pending additional analysis of overall survival, data on overall survival and objective response rates remained blinded.

Adverse Events

Grade 3 or 4 adverse events occurred in 40.3% of the relatlimab/nivolumab group vs 33.4% of the nivolumab-alone 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 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. Dr. Tawbi has received research support from Bristol Myers Squibb, Genentech, GlaxoSmithKline, Merck Sharp & Dohme, and Novartis; has served as a consultant to Bristol Myers Squibb, Eisai, Genentech, Karyopharm Therapeutics, Merck Sharp & Dohme, and Novartis; and has received writing support from Bristol Myers Squibb.

REFERENCE

1. Tawbi HA, Schadendorf D, Lipson EJ, et al: Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med 386:24-34, 2022.