The addition of the lymphocyte activation gene-3 (LAG-3)–blocking antibody relatlimab to nivolumab (Opdivo) led to significantly longer progression-free survival (PFS) compared with nivolumab alone in previously untreated patients with advanced melanoma, according to results of the phase 3 RELATIVITY-047 clinical trial presented at the ASCO 2021 virtual annual meeting.
“Our findings demonstrate that combination therapy with relatlimab and nivolumab is a potential novel treatment option for this patient population,” said the study’s lead investigator Evan J. Lipson, MD, Associate Professor, Medical Oncology, Melanoma and Cancer Immunology Programs, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD. “In addition, our results further validate a LAG-3 immune checkpoint as a therapeutic target in cancer and support the continued development of relatlimab in patients with other malignancies,” he added.
LAG-3 is an immune checkpoint inhibitor that inhibits T-cell activity and is upregulated in melanoma and other tumor types. Relatlimab is a human LAG-3–blocking antibody that restores effector function of exhausted T-cells, thereby reinvigorating an antitumor response. Preclinical models have demonstrated synergistic antitumor activity of dual inhibition of LAG-3 and PD-1, and early-phase clinical trials have shown durable objective responses in patients with melanoma that was relapsed or refractory to anti–PD-1 therapy.
Study Details
The RELATIVITY-047 trial randomized 714 patients with previously untreated unresectable or metastatic melanoma in a 1:1 ratio to a fixed-dose combination of 160 mg relatlimab plus 480 mg nivolumab every 4 weeks, or nivolumab alone. Previous exposure to systemic neoadjuvant or adjuvant therapy was limited to 8.4% of the study population.
The primary end point was PFS for all study participants and for subgroups; secondary end points were overall survival and objective response rate.
“The study population exhibited several characteristics often associated with poor prognosis, including approximately 40% of patients with visceral or brain metastases…approximately 36% had an elevated serum lactate dehydrogenase [LDH] level, and 60% of tumors had PD-L1 [PD ligand 1] expression <1%,” Dr Lipson said.
Median duration of therapy was 5.6 months in the combination arm and 4.9 months in the nivolumab monotherapy arm. At a median follow-up of 13.2 months, median PFS per blinded independent review was 10.1 months in patients treated with relatlimab plus nivolumab and 4.6 months in those treated with nivolumab alone (hazard ratio, 0.75; P = .0055), thus meeting the study’s primary end point. At 1 year, PFS rates were 47.7% for patients in the combination arm and 36.0% for those in the nivolumab monotherapy arm.
“The PFS benefit appeared relatively early in the course of therapy” with the PFS curves diverging at 12 weeks, Dr Lipson said.
Median PFS was improved with the combination therapy across prespecified subgroups stratified by LDH level, tumor burden, BRAF mutation status, and expression of LAG-3 and PD-L1 in the tumor microenvironment.
“The PFS benefit associated with relatlimab plus nivolumab was observed regardless of LAG-3 expression status using a 1% cutoff,” which suggests that “LAG-3 expression alone does not predict benefit from relatlimab plus nivolumab, although there was a trend toward improved median PFS observed among LAG-3 expressors in both arms,” he said.
Safety Profile
Grade 3/4 adverse events (AEs) were reported in 40.3% of patients in the relatlimab plus nivolumab arm and 33.4% of patients in the nivolumab arm. Treatment-related AEs that led to discontinuation occurred in 14.6% and 6.7% of patients, respectively. Immune-mediated AEs were typical and manageable, generally supporting a favorable safety profile for relatlimab plus nivolumab.
Expert Commentary
“Relatlimab is a new standard of care that I think should replace anti–PD-1 antibody alone. This combination of relatlimab plus nivolumab has a statistically significant and clinically meaningful improvement in PFS. Toxicity is manageable above anti–PD-1 monotherapy,” commented Jason J. Luke, MD, FACP, Director, Cancer Immunotherapeutics Center, University of Pittsburgh Medical Center Hillman Cancer Center, PA.