The combination of nivolumab and relatlimab continues to demonstrate a progression-free survival (PFS) benefit compared to nivolumab alone in patients with previously untreated metastatic or unresectable melanoma. In addition, for the first time, the dual checkpoint inhibitor therapy also demonstrated a higher overall response rate (ORR), according to follow-up data from the RELATIVITY-047 trial.
Previously, the RELATIVITY-047, a global, randomized, double-blind, Phase II/III study, had met its primary endpoint of PFS after 13.2 months follow-up (J Clin Oncol 2021; doi: 10.1200/JCO.2021.39.15_suppl.9503). Relatlimab, a human LAG-3 blocking antibody, and nivolumab, an anti-PD-1 agent, as a fixed-dose combination demonstrated a significant PFS benefit, with a median PFS of 10.1 months with the combination versus 4.6 months with nivolumab monotherapy, with a manageable safety profile.
At an American Society of Clinical Oncology (ASCO) Plenary Series session in March 2022, lead author Georgina V. Long, MD, FRACP, PhD, Chair of Melanoma Medical Oncology and Translational Research at the Melanoma Institute Australia at the University of Sydney, presented updated PFS results and the first disclosure of secondary endpoints, including overall survival (OS) and ORR.
"Nivolumab plus relatlimab continue to improve PFS versus nivolumab alone. The PFS favored the combination for all stratification factors," Long stated. Key stratification factors included LAG-3 expression on immune cells in the tumor microenvironment, PD-L1 expression on tumor cells, BRAF mutational status, and AJCC v8 M stage.
Study Details
In this Phase II/III trial, 714 patients, median age 63 years, with previously untreated, unresectable, or metastatic melanoma who had an ECOG performance status of 0 or 1 were randomized to receive nivolumab plus relatlimab (355 patients) or nivolumab (359 patients). They received the fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg given every 4 weeks versus nivolumab alone at the same dose and schedule. Patient characteristics were well-balanced, Long said.
After a median follow up of 19.3 months, the updated median PFS was 10.2 months with the combination compared to 4.6 months with nivolumab alone. The OS benefit with dual therapy was not statistically significant over monotherapy. However, "there was clinically meaningful improvement in OS with nivolumab and relatlimab, representing a 20 percent improvement in the risk of death," said Long.
OS rates were 77 percent versus 71.6 percent at 12 months, 63.7 percent versus 58.3 percent at 24 months, and 55.8 percent versus 48.8 percent at 36 months, respectively. Median OS was not yet reached with nivolumab and relatlimab compared to 34.1 months with nivolumab.
Confirmed ORR was 43.1 percent with the combination versus 32.6 percent with monotherapy. Complete responses were observed in 16.3 percent of patients on nivolumab and relatlimab versus 14.2 percent on nivolumab. The median duration of response was not reached in either arm. The use of subsequent systemic therapy was lower among those taking the combination, Long noted.
More Grade 3/4 treatment-related adverse events (TRAEs) were observed in the nivolumab plus relatlimab arm (21.1%) compared to the nivolumab arm (11.1%). TRAEs in the combination arm consisted of thyroid disruptions, rash, diarrhea, and colitis. There were four treatment-related deaths in the nivolumab plus relatlimab group and two in the nivolumab group. TRAEs leading to treatment discontinuation were observed in 15.2 percent of patients treated with nivolumab and relatlimab and 7.2 percent of patients treated with nivolumab.
The types of adverse events associated with the combination are similar to those seen with other immune-oncology agents and no new information on any new or known adverse events were observed, she said.
"These findings provide additional evidence of the benefit of two checkpoint inhibitors over only one and supports the combination of nivolumab and relatlimab, which had a manageable safety profile, as a potential new treatment option for patients with advanced melanoma," Long shared.
In summary, she noted: "RELATIVITY-047 met its primary endpoint and demonstrated a superior PFS benefit versus nivolumab. Nivolumab plus relatlimab continued to demonstrate consistent PFS benefit with longer follow-up, with a 22 percent reduction in the risk of progression or death. These data further validate nivolumab plus relatlimab as a potential new treatment option in patients with advanced melanoma and support the benefit of dual checkpoint inhibition."
Allison Betof Warner, MD, PhD, ASCO Expert in Melanoma and Medical Oncologist at Memorial Sloan Kettering Cancer Center, shared her thoughts on the study. "The updated data from RELATIVITY-047 further support the use of nivolumab plus relatlimab over single agent anti-PD-1 therapy for patients who have previously untreated advanced melanoma," she noted. "Combination therapy demonstrated higher ORR and continued to show superior PFS compared to nivolumab in exchange for only a modest increase in side effects. If approved, I expect that nivolumab plus relatlimab will become a standard first-line regimen for the treatment of unresectable or metastatic melanoma."
ASCO discussant Adil Daud, MD, Director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center, offered some thoughts. "RELATIVITY-047 marks a major advance for immunotherapy beyond CTLA-4 and PD-L1. OS was not statistically significant at this time, although numerically appears to be better. ORR and CR also appear to be better for nivolumab plus relatlimab."
The combination of nivolumab plus relatlimab maintains some efficacy as compared to ipilimumab plus nivolumab, which has a high toxicity rate, but questions about the long-term efficacy and activity of nivolumab plus relatlimab in brain metastases need to be answered, he noted.
Mark L. Fuerst is a contributing writer.