Positive results from the Phase II/III, pivotal RELATIVITY-047 clinical trial studying the combination therapy of Bristol Myers Squibb (BMS)’s approved immune checkpoint inhibitor (ICI), Opdivo (nivolumab), and its pipeline monoclonal antibody, relatlimab were recently published in The New England Journal of Medicine. Patients with untreated advanced (unresectable or metastatic) melanoma were randomised in this trial to receive either Opdivo + relatlimab or Opdivo monotherapy. The trial met its primary endpoint of progression-free survival (PFS), which was assessed by blinded independent central review.

First-line therapy for melanoma consists of ICIs such as the anti-programmed cell death protein-1 (PD-1) ICI, Opdivo. Many patients respond well to ICIs, but approximately 50% of patients progress, therefore novel agents, which work synergistically with approved ICIs to improve the antitumor response, would broaden the viable therapeutic options for these patients. The BMS pipeline agent relatlimab targets the immune checkpoint lymphocyte activation gene-3 (LAG-3), a co-inhibitory receptor that suppresses T-cell activation. In the Phase I/II NCT01968109 trial, the combination therapy of Opdivo + relatlimab showed efficacy in patients who progressed after anti-PD-1 therapy. BMS attempted to replicate this success in the first-line setting. Patients who were treated with Opdivo + relatlimab in the RELATIVITY-047 trial had a median PFS of 10.1 months compared to 4.6 months for patients who received Opdivo monotherapy. Notably, the combination therapy had a manageable safety profile with 18.9% and 9.7% of patients reporting grade 3 or 4 treatment-related adverse events in the Opdivo + relatlimab and Opdivo monotherapy arms, respectively.

However, many experts remain sceptical about the success of this combination. Firstly, the interaction between the LAG-3 receptor and T-cells is not fully understood. Secondly, it is difficult to predict who will respond to this combination therapy. Given that patients in the Phase I/II trial with ≥1% LAG-3 expression in tumour-associated immune cells showed nearly a three-fold improvement in overall response rate (ORR) compared to patients with <1% LAG-3 expression when treated with Opdivo + relatlimab, key opinion leaders (KOLs) that were interviewed for GlobalData’s Melanoma – Global Drug Forecast and Market Analysis to 2029 report believe that success of this combination therapy could be restricted to this patient subgroup.  

Nonetheless, the European Medicines Agency (EMA) is currently reviewing Opdivo + relatlimab for the first-line treatment of advanced melanoma and GlobalData expects this combination to gain regulatory approval by July of this year. Jonathan Clegg, senior vice-president and head of the Oncology Department at BMS, believes that this combination therapy can revolutionise the melanoma market, stating that “this treatment would become the first of its kind available to patients in the EU.” According to GlobalData’s patient-based melanoma forecast, Opdivo + relatlimab sales in the five major European markets (France, Germany, Italy, Spain and the UK) in the first-line setting are expected to reach $9 million by 2029 if approved.