Efficacy was seen with blocking LAG-3 in combination with PD-1 as a therapeutic strategy for patients with melanoma. Additionally, this research establishes LAG-3 as the third immune checkpoint pathway to have proven clinical benefit in this patient population.
The combination of relatlimab and nivolumab (Opdivo) for untreated advanced melanoma significantly improves progression-free survival (PFS) compared with nivolumab monotherapy, according to a phase 2/3 study conducted by MD Anderson Cancer Center and published in The New England Journal of Medicine.1,2
Both LAG-3 and PD-1 are upregulated in melanoma, leading to T-cell exhaustion. Relatlimab is a LAG-3 inhibitor and nivolumab is an anti-PD-1, supporting their combination in this patient population.
“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 Hussein Tawbi, MD, PhD, professor of Melanoma Medical Oncology at MD Anderson, in a press release.1 “We’ve 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.”
The phase 2/3 study (NCT03470922) has an actual enrollment of 714 participants and an estimated completion date of November 2023. The primary end point of the study is progression-free survival (PFS). Secondary end points include overall survival (OS) and overall response rate (ORR). Other end points explored include the incidence of adverse events (AEs), severity of AEs, incidence of AEs leading to discontinuation, incidence of deaths, and incidences in clinically significant changes in clinical laboratory results.2,3
During the study, patients were randomized into 1 of 2 arms. In arm 1, patients received the experimental combination of relatlimab and nivolumab. In arm 2, patients received nivolumab monotherapy.
In the combination arm (n = 355), the median age was 63 (range, 20-94) and 40.8% were female. Metastasis stages included M0 (9.9%). M1a or b (45.65), M1c (42.5%), and M1d (1.7%). Melanoma subtypes included cutaneous acral (11.5%), cutaneous nonacral (70.1%), mucosal (6.5%), and other (11.8%). Sixty-six percent of patients had an ECOG performance status of 0 and the median tumor burden was 59 (range, 10-317). Seventy-five percent of patients had a LAG-3 expression of 1% or more and 58.9% of patients had a PD-L1 expression of less than 1%. Over 61% of patients did not have a BRAF mutation.
In the monotherapy arm, the median age was 62 (range, 21-90) and 42.6% were female. Metastasis stages included M0 (6.4%), M1a or b (54.3%), M1c (35.4%), and M1d (3.1%). Melanoma subtypes included cutaneous acral (11.4%), cutaneous nonacral (70.8%), mucosal (7.8%), and other (10%).
In the combination arm, the median PFS was 10.12 months (range, 6.37-15.74) compared with 4.63 months in the monotherapy arm (3.36-5.62). For patients with a LAG-3 expression of 1% or greater, the median PFS with the combination was 12.58 months (range, 6.67-23.10) and 4.76 months (range, 4.47-8.61) with the monotherapy. For patients with a LAG-3 expression of less than 1%, median PFS with the combination was 4.83 (range, 3.86-10.05) compared with 2.79 months with the monotherapy (range, 2.79-4.63).
In terms of safety, grade 3 or 4 treatment-related AEs were seen in 18.9% of patients in the combination arm and 9.7% of patients in the monotherapy arm. The most common grade 3/4 AEs included increased levels of pancreatic and liver enzymes, and fatigue. Three deaths in the combination arm and 2 deaths in the monotherapy arm were found to be treatment-related.
“We now have evidence of a clear benefit for combination therapy compared to single-agent PD-1 inhibitors, and we’re looking forward to seeing response and overall survival data,” said Tawbi, in the press release.1“We’re 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’re making against melanoma.”