麻豆传媒

A dual immunotherapy regimen targeting the novel lymphocyte-activation gene 3 (LAG-3) immune checkpoint led to a significant progression-free survival (PFS) benefit in patients with advanced melanoma, according to a phase III study.

At a median follow-up of 13.2 months, the combination of the anti-LAG-3 antibody relatlimab and the PD-1 inhibitor nivolumab (Opdivo) extended PFS to 10.1 months, as compared with 4.6 months with nivolumab alone (HR 0.75, 95% CI 0.6-0.9, P=0.0055), reported Evan Lipson, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

"Relatlimab and nivolumab is a potential novel treatment option for this patient population," said Lipson during a press briefing held in advance of the virtual American Society of Clinical Oncology (ASCO) annual meeting.

"Additionally -- and importantly -- this is the first phase III study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy for patients with cancer, and it established the LAG-3 pathway as the third immune checkpoint pathway in history after CTLA-4 and PD-1, for which blockage appears to have clinical benefit," he added.

While the introduction of drugs targeting the PD-1 immune checkpoint pathway has improved survival rates for patients with a variety of cancers, including melanoma, Lipson said that the objective of this study was to build on that success by combining the PD-1 inhibitor nivolumab with relatlimab, a human IgG4 LAG-3-blocking antibody that restores effector function of exhausted T cells.

"Although these drugs work through distinct pathways, they have a common goal," said Lipson, "which is to unleash and attack by immune T cells against cancer." He pointed out that earlier studies have showed that combining the two drugs caused tumors to shrink in some patients with advanced melanoma that had already progressed through anti-PD-1 treatment alone.

In the RELATIVITY-047 trial, 714 patients with previously untreated, unresectable, or metastatic melanoma and similar baseline characteristics were randomized 1:1 to receive relatlimab (160 mg) plus nivolumab (480 mg) every 4 weeks, or nivolumab alone (480 mg) every 4 weeks. Relatlimab and nivolumab were administered as a single intravenous infusion, in order to reduce preparation and infusion times, as well as reduce the risk of administration error, Lipson said.

The primary endpoint was PFS per RECIST version 1.1 as assessed by blinded independent central review.

At 12 months, the PFS rates were 47.7% for the combination group and 36.0% for nivolumab-alone group.

Adverse events associated with the combination were "manageable and reflected the safety profile we typically see with immune checkpoint inhibitors," Lipson noted.

Specifically, the incidence of grade 3/4 treatment-related adverse events (TRAEs) in the relatlimab/nivolumab group was double that observed in the nivolumab-alone group (18.9% vs 9.7%). However, Lipson pointed out that these adverse events occurred at a lower rate than has been seen with other immunotherapy combinations.

There were three treatment-related deaths in the combination group and two in the nivolumab group. TRAEs of any kind led to treatment discontinuation in 14.6% and 6.7% of patients, respectively.

The combination has "the potential to change practice" if approved, commented ASCO Chief Medical Officer and Executive Vice President Julie Gralow, MD, of the University of Washington in Seattle. She also noted that melanoma "has been a big home run for immune checkpoint agents, where if you were going to see a signal of a benefit from adding these two agents together, it would be in one of these cancers where we've seen such activity in general."

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