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The European Commission has approved the fixed-dose combination of relatlimab plus nivolumab for use in the frontline treatment of select patients with advanced or metastatic melanoma and a PD-L1 expression of less than 1% on tumor cells.
The European Commission has approved the fixed-dose combination of relatlimab plus nivolumab (Opdivo; Opdualag) for use in the frontline treatment of adult and adolescent patients aged 12 years of age and older with advanced or metastatic melanoma and a PD-L1 expression of less than 1% on tumor cells.1
The regulatory decision was supported by data from an exploratory analysis of the phase 2/3 RELATIVITY-047 trial (NCT03470922), in which the regimen resulted in a median progression-free survival (PFS) that was more than double that achieved with single-agent nivolumab in this patient population. The median PFS in the investigative arm was 6.7 months (95% CI, 4.7-12.0) vs 3.0 months (95% CI, 2.8-4.5) in the control arm (HR, 0.68; 95% CI, 0.52-0.86).
Moreover, the median overall survival (OS) in those who received relatlimab plus nivolumab has not been reached (HR, 0.78; 95% CI, 0.59-1.04).
With this approval, the combination can be used in this population in all European Union states, Iceland, Liechtenstein, and Norway.
“Opdualag is now the first approved LAG-3–blocking antibody combination for advanced melanoma in the European Union. The RELATIVITY-047 study demonstrated the important benefit of inhibiting both LAG-3 and PD-L1 with our novel immunotherapy combination,” Samit Hirawat, MD, executive vice president and chief medical officer of Global Drug Development at Bristol Myers Squibb, stated in a press release. “This is a continuation of our work in bringing innovative medicines to adults and adolescents living with melanoma.”
A total of 714 patients with previously untreated, unresectable, or metastatic melanoma who had an ECOG performance status of 0 or 1 were enrolled to the global, randomized, double-blind RELATIVITY-047 trial. Those with active autoimmune disease, medical conditions in need of systemic treatment with moderate- or high-dose corticosteroids or immunosuppressive agents, uveal melanoma, or active or untreated brain or leptomeningeal metastases, were excluded.
Participants were randomly assigned 1:1 to nivolumab at 480 mg in combination with relatlimab at 160 mg every 4 weeks (n = 355) or single-agent nivolumab at 480 mg every 4 weeks (n = 359). Treatment was given until disease progression, intolerable toxicity, or withdrawn consent. Stratification factors included LAG-3 expression on immune cells in the tumor microenvironment, PD-L1 expression on tumor cells, BRAF mutational status, and AJCC v8 metastatic stage.
PFS by blinded independent central review (BICR) served as the primary end point of the research. Key secondary endpoints comprised OS and objective response rate (ORR) by BICR. End points were hierarchically tested beginning with PFS, then OS, followed by ORR.
The FDA approved relatlimab plus nivolumab in March 2022 for use in adult and pediatric patients aged 12 years and older with unresectable or metastatic melanoma.2 The approval was based on earlier data from RELATIVITY-047, in which the combination resulted in a median PFS of 10.1 months (95% CI, 6.4-15.7) vs 4.6 months (95% CI, 3.4-5.6) with the monotherapy (HR, 0.75; 95% CI, 0.62-0.92; P = .0055).
Updated findings demonstrated that at a median follow-up of 19.3 months, the PFS benefit derived with relatlimab plus nivolumab was maintained.3 Specifically, those in the investigative and the control arms had a median PFS of 10.22 months (95% CI, 6.51-14.75) and 4.63 (95% CI, 3.48-6.44), respectively (HR, 0.78; 95% CI, 0.64-0.94). The 24-month PFS rates were 38.5% (95% CI, 32.7%-44.2%) and 29.0% (95% CI, 23.8%-34.4%), respectively.
The combination induced an ORR of 43.1% (95% CI, 37.9%-48.4%) by BICR vs 32.6% (95% CI, 27.8%-37.7%) with the monotherapy; this translated 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). Among those who received relatlimab plus nivolumab, 16.3% achieved a complete response, 26.8% experienced a partial response, and 18.2% had stable disease.
Regarding safety, the most common adverse effects (AEs) experienced with relatlimab plus nivolumab included fatigue (41%), musculoskeletal pain (32%), rash (29%), arthralgia (26%), diarrhea (26%), pruritus (26%), headache (20%), nausea (19%), cough (16%), reduced appetite (16%), hypothyroidism (16%), abdominal pain (14%), vitiligo (13%), pyrexia (12%), constipation (11%), urinary tract infection (11%), dyspnea (10%), and vomiting (10%).
Serious AEs that were most frequently experienced in the combination arm included adrenal insufficiency (1.4%), anemia (1.4%), back pain (1.1%), colitis (1.1%), diarrhea (1.1%), myocarditis (1.1%), pneumonia (1.1%), and urinary tract infection (1.1%).
Adverse reactions that were grade 3 to 5 in severity occurred in 43% of those in the combination arm vs 35% of those in the monotherapy arm.