Relatlimab-nivolumab combo boosts PFS in advanced melanoma

A novel immune checkpoint inhibitor combination of relatlimab and nivolumab significantly extends progression-free survival (PFS) vs nivolumab alone in patients with untreated advanced melanoma in the phase II/III RELATIVITY-047 trial.

Median PFS on blinded independent central review was significantly longer with the combination treatment vs nivolumab alone (10.1 months vs 4.6 months, hazard ratio [HR], 0.75; p= 0.0055). At 12 months, the PFS rate was 47.7 percent among patients given relatlimab plus nivolumab vs 36.0 percent among those given nivolumab alone.

“This makes relatlimab plus nivolumab a potential new treatment option for this patient population,” said lead investigator Dr Evan Lipson from the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine in Baltimore, Maryland, US, at ASCO 2021.

PFS benefit appeared early

Seven-hundred fourteen patients with previously untreated unresectable or metastatic melanoma were randomly assigned to relatlimab 160 mg plus nivolumab 480 mg, given as a single intravenous infusion every 4 weeks (Q4W), or intravenous nivolumab 480 mg alone, given Q4W. Patient characteristics were well balanced between the two treatment groups. The primary endpoint was PFS per RECIST v1.1 as assessed by blinded independent central review. The median follow-up was 13.2 months.  [ASCO 2021, abstract 9503]

“The PFS benefit appeared early, with the curves separating at 12 weeks, and was sustained over the course of follow-up,” said Lipson.

As for nivolumab monotherapy, performance was similar to what was seen for the drug in previous nivolumab trials. However, he said cross-trial comparison remains difficult owing to differences in study design.

Safety profile

“Treatment-related adverse events [TRAEs] associated with the combination treatment were manageable,” said Lipson. “These reflected the safety profile we typically see with immune checkpoint inhibitors.”

Over 40 percent of patients on combination therapy experienced a grade 3–4 adverse event vs 33.4 percent of those given nivolumab alone. Grade 3–4 TRAEs that led to treatment discontinuation occurred in 8.5 percent and 3.1 percent of patients, respectively. There were 3 treatment-related deaths in the relatlimab and nivolumab arm and 2 in the nivolumab-alone arm.

LAG-3 inhibition in cancer

Currently available immune checkpoint inhibitors, such as nivolumab and similar agents, act as inhibitors of the programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1).  By contrast, relatlimab acts as an antibody that targets LAG-3, which inhibits T cells and helps cancer cells evade immune attacks.

“Ours is the first phase III study of a novel fixed-dose combination to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways,” Lipson said at a press briefing prior to the presentation. “The RELATIVITY-047 trial also establishes the LAG-3 pathway as the third immune checkpoint pathway in history, after CLTA-4 and PD-1, for which blockade appears to have a clinical benefit.”

When sought for comment, Dr Julie Gralow, chief medical officer and executive vice-president of ASCO, agreed the results validated the LAG-3 immune checkpoint as a therapeutic target in advanced melanoma. “However, the combination therapy was clearly more toxic,” she said. “So, I think there will be a lot of discussions around here on when it should be used, and for which patients.”

Whether PFS would be a surrogate for an overall survival benefit also remains to be seen.