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The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of the fixed-dose combination of nivolumab and relatlimab for the frontline treatment of adult and adolescents who are 12 years of age or older with advanced melanoma and a tumor cell PD-L1 expression of less than 1%.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of the fixed-dose combination of nivolumab (Opdivo) and relatlimab (Opdualog) for the frontline treatment of adult and adolescents who are 12 years of age or older with advanced melanoma and a tumor cell PD-L1 expression of less than 1%.1
The proposed indication was supported by findings from an exploratory analysis of patients with a PD-L1 expression of less than 1% who were examined in the phase 2/3 RELATIVITY-047 trial (NCT03470922).
Data presented during the 2022 ASCO Annual Meeting showed that the hazard ratio (HR) for progression-free survival (PFS) by blinded independent central review (BICR) in those with a PD-L1 expression of less than 1% (n = 209) was 0.68 (95% CI, 0.53-0.86). The HR for overall survival (OS) in this subset was 0.78 (95% CI, 0.59-1.04).2
“We are very proud of the role we have played in progressing the treatment of advanced melanoma over the years. As part of our mission to deliver new medicines for patients, we have continued to develop new dual immunotherapy combinations,” Paul Basciano, development lead of relatlimab at Bristol Myers Squibb (BMS), stated in a press release. “This positive CHMP opinion marks the first step toward the potential approval of the first LAG-3–blocking antibody combination – and the third distinct checkpoint inhibitor for BMS – for advanced melanoma patients in the European Union.”
The global, randomized, double-blind, gated, phase 2/3 RELATIVITY-047 trial enrolled patients with previously untreated, unresectable, or metastatic melanoma who had an ECOG performance status of 0 or 1.
A total of 714 study participants were randomized 1:1 to receive the fixed-dose combination of nivolumab at 480 mg plus relatlimab at 160 mg intravenously (IV) every 4 weeks (n = 355) or IV nivolumab at 480 mg every 4 weeks (n = 359).
Patients were stratified by LAG-3 expression on immune cells in the tumor microenvironment, PD-L1 expression on tumor cells, BRAF mutational status, and AJCC v8 metastatic stage.
The primary end point of the trial was PFS by BICR, and secondary end points included OS and objective response rate (ORR) by BICR. Moreover, end points were hierarchically tested starting with PFS, followed by OS, and then ORR.
The median age of patients was 63 years (range, 20-94), and 41.7% were female. Regarding AJCC v8 M stage, 25.8% had M1A stage, 24.2% had M1B stage, 38.9% had M1C stage, and 2.4% had M1D stage. Additionally, 66.9% of patients had an ECOG performance status of 0, 36.1% had a serum lactate dehydrogenase level above the upper limit of normal, and 8.4% previously received neoadjuvant or adjuvant treatment.
Regarding LAG-3 expression, 75.2% of patients had expression of 1% or higher and 24.8% had expression of less than 1%. Forty-one percent of patients had a PD-L1 expression of 1% or higher and 59% had an expression of less than 1%. Regarding BRAF mutational status, 38.5% had mutated disease, and 61.5% had wild-type disease. Moreover, 65.7% of patients had AJCC M stage of M0/M1any and 34.3% had M1any.
In March 2022, the FDA approved relatlimab plus nivolumab for the treatment of adult and pediatric patients aged 12 years and older with unresectable or metastatic melanoma.3 The decision was supported by earlier findings from the trial, which showed that the doublet resulted in a median PFS of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) with standard nivolumab monotherapy (HR, 0.75; 95% CI, 0.62-0.92; P = .0055).
Updated data showed that at a median follow-up of 19.3 months, the PFS benefits achieved with the combination were maintained.2 The median PFS with nivolumab/relatlimab was 10.22 months (95% CI, 6.51-14.75) vs 4.63 months (95% CI, 3.48-6.44) with single-agent nivolumab (HR, 0.78; 95% CI, 0.64-0.94).
The 12-month PFS rates in the investigative and control arms were 48.0% (95% CI, 42.5%-53.4%) and 36.9% (95% CI, 31.7%-42.1%), respectively; at 24 months, these rates were 38.5% (95% CI, 32.7%-44.2%) and 29.0% (95% CI, 23.8%-34.4%), respectively.
With 19.3 months of follow-up, the doublet resulted in a clinically meaningful improvement in OS vs nivolumab monotherapy, although this improvement was not determined to be of statistical significance. In those who received the doublet, the median OS had not yet been reached (NR; 95% CI, 34.20-NR) vs 34.10 months (95% CI, 25.23-NR) in those who received nivolumab alone (HR, 0.80; 95% CI, 0.64-1.01; P = .0593).
The 12-month OS rates in the investigative and control arms were 77.0% (95% CI, 72.2%-81.1%) and 71.6% (95% CI, 66.6%-76.0%), respectively, and the 24-month OS rates were 63.7% (95% CI, 58.1%-68.7%) and 58.3% (95% CI, 52.7%-63.4%), respectively. The 36-month OS rates in these arms were 55.8% (95% CI, 49.8%-61.4%) and 48.8% (95% CI, 42.7%-54.7%), respectively.
Additionally, the doublet elicited an ORR of 43.1% (95% CI, 37.9%-48.4%) per BICR vs 32.6% (95% CI, 27.8%-37.7%) with nivolumab monotherapy, translating to a 10.3% difference between the arms (95% CI, 3.4-17.3) with an odds ratio of 1.6 (95% CI, 1.2-2.2). In the combination arm, 16.3% achieved a complete response (CR), 26.8% had a partial response (PR), and 18.2% achieved stable disease; in the monotherapy arm, the CR rate was 14.2%, the PR rate was 18.4%, and the stable disease rate was 16.4%. Those in the investigative arm experienced a lower rate of progressive disease than those in the control arm, at 29.6% vs 41.5%, respectively.
Common treatment-related toxicities included pruritus, fatigue, rash, hypothyroidism, arthralgia, diarrhea, and vitiligo. Any-grade treatment-related adverse effects (TRAEs) were reported in 83.7% of those in the combination arm and 72.4% of those in the monotherapy arm; they led to discontinuation in 15.2% and 7.2% of patients, respectively.
Grade 3 or 4 TRAEs were reported in 21.1% and 11.1% of those in the investigative and control arms, respectively; these effects resulted in discontinuation in 9.0% and 3.6% of patients, respectively. Treatment-related deaths occurred in 4 patients in the investigative arm and 2 patients in the control arm.