Combination LAG-3/PD-1 inhibition superior to PD-1 inhibition monotherapy for metastatic melanoma

Findings from a new study suggest that inhibiting both the LAG-3 and PD-1 immune checkpoints in patients with previously untreated metastatic melanoma or unresectable melanoma provided greater benefit toward progression-free survival than inhibition of PD-1 alone.


These findings were published in The New England Journal of Medicine (Jan. 6, 2022; 386:24-34).


In the study, patients with previously untreated metastatic or unresectable melanoma were treated with either relatlimab and nivolumab as a fixed-dose combination or nivolumab alone, administered intravenously every four weeks. The primary endpoint was progression-free survival as assessed by blinded independent central review.


The investigators observed median progression-free survival of 10.1 months in the combination arm and 4.6 months in the monotherapy arm. After 12 months of follow-up, progression-free survival rates were 47.7% in the combination arm versus 36% in the monotherapy arm, with a 25% lower risk of disease progression or death in the combination arm.


“The results from this global effort advance the field of immunotherapy by establishing a third class of immune checkpoint inhibitors through the LAG-3 pathway and have the potential to be practice-changing,” said lead author Dr. Hussein Tawbi, in a press release. “We have seen historic developments in melanoma treatment over the last decade with the combination of PD-1 and CTLA-4 inhibitors, which work well but also carry substantial toxicity. This study represents a significant and long-awaited next step toward providing patients with effective and safer treatment options.” Dr. Tawbi is a professor of Melanoma Medical Oncology at the University of Texas M. D. Anderson Cancer Center in Houston.


Some 18.9% of patients in the combination arm and 9.7% in the monotherapy arm experienced grade 3 or 4 treatment-related adverse events. The most common of these adverse events included increased levels of pancreatic and liver enzymes and fatigue. Investigators determined three deaths in the combination arm and two deaths in the monotherapy arm were treatment-related. Immune-mediated adverse events included hypothyroidism/thyroiditis, rash and colitis. No new safety signals were identified, and patients rated their health-related quality of life similarly across both treatment arms.


Some 65.8% of patients had discontinued treatment by the time of data cutoff on March 9, 2021. The top reason for discontinuation was disease progression, which was less common in the combination arm (36.3%) compared with the monotherapy arm (46%).


“We now have evidence of a clear benefit for combination therapy compared to single-agent PD-1 inhibitors, and we are looking forward to seeing response and overall survival data,” Dr. Tawbi said. “We are also thinking about the populations that were excluded from this trial, including those with untreated brain metastases and uveal melanoma, so that all patients can have a chance to take advantage of the progress we are making against melanoma.”

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