A novel immunotherapeutic combination that targets PD-1 and the LAG-3 pathway may significantly delay disease progression as a first-line treatment of advanced or unresectable melanoma. Updated results of the global phase III RELATIVITY-047 trial validated the study’s initial findings and were presented in the March 2022 session of the ASCO Plenary Series by Georgina V. Long, MD, PhD, of the Melanoma Institute Australia, Sydney (Abstract 360385).

In the study, nivolumab and relatlimab were given as a fixed-dose combination to 714 previously untreated patients with advanced or metastatic melanoma. Dr. Long reported updated findings for progression-free survival, as well as the first data on the secondary endpoints of overall survival and overall response rate.

These data further validate this combination as a potential new treatment option in patients with advanced melanoma and support the benefit of dual checkpoint inhibition.

— Georgina V. Long, MD, PhD

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“At this analysis, with additional longer follow-up, nivolumab plus relatlimab continued to demonstrate a consistent benefit in improving progression-free survival compared with nivolumab alone. The hazard ratio was 0.78, representing a 22% reduction in the risk of [disease] progression or death with the combination. The progression-free survival favored the nivolumab/relatlimab combination for all stratification factors, and overall survival rates were numerically improved at 12, 14, and 36 months vs nivolumab alone,” Dr. Long said. “These data further validate this combination as a potential new treatment option in patients with advanced melanoma and support the benefit of dual checkpoint inhibition.”

About RELATIVITY-047

Lymphocyte-activation gene 3 (LAG-3) upregulates an immune checkpoint pathway that inhibits T-cell activity. Relatlimab, a human IgG4 LAG-3–blocking antibody, restores the effector function of exhausted T cells and reinvigorates the T cells to attack the tumor. The combination of relatlimab and the anti–PD-1 agent nivolumab modulates potentially synergistic immune checkpoint pathways, and this is thought to enhance antitumor immune responses.

RELATIVITY-047 is a global double-blind randomized registrational phase III study evaluating a fixed-dose combination of nivolumab and relatlimab in 714 treatment-naive patients with advanced melanoma. Approximately 40% of the population had M1C or M1D metastatic melanoma, 67% had a performance status of 0, and < 10% had been treated with prior neoadjuvant or adjuvant therapy. At baseline, 36% of patients had elevated lactate dehydrogenase, 75% had LAG-3 expression of ≥ 1%, 59% had PD-L1 expression of < 1%, and 38% had BRAF mutations.

Patients were randomly assigned 1:1 to every-4-week intravenous administration of relatlimab at 160 mg plus nivolumab at 480 mg or nivolumab at 480 mg, stratified by LAG-3 expression, PD-L1 expression, BRAF mutation status, and disease stage.

In the initial analysis, after a median follow-up of 13.2 months, the study met its primary endpoint by significantly improving median progression-free survival vs nivolumab alone. By blinded independent review, median progression-free survival was 10.2 vs 4.6 months (hazard ratio [HR] = 0.75, P = .0055).

Initial Findings Upheld

In the updated analysis, after a median follow-up of 19.3 months, the outcomes were virtually identical to the initial analysis. Median progression-free survival was 10.2 months with relatlimab/nivolumab vs 4.6 months with nivolumab (HR = 0.78, 95% confidence interval [CI] = 0.64–0.94). Percentage progression-free was 48.0% and 36.9%, respectively, at 12 months, and 38.5% and 29.0% at 24 months, Dr. Long reported.

Median overall survival was not reached with the combination and was 34.1 months with nivolumab alone (HR = 0.80, P = .0593). Overall survival rates were 77.0% and 71.6%, respectively, at 12 months; 63.7% and 58.3% at 24 months; and 55.8% and 48.8% at 36 months.

The boundary for statistical significance was P < .04302 (2-sided) based on 69% power for a target hazard ratio of 0.75; therefore, statistical significance was not met, but the difference is “clinically meaningful,” Dr. Long commented. The benefit was observed across all stratification factors.

The combination also increased the overall response rates: 43.1% vs 32.6% (complete response rates were 16.3% and 14.2%). The difference of 10.6% in the overall response rate translated into an odds ratio of 1.6; median duration of response was not reached in either arm, Dr. Long said.

Manageable Safety Profile

Treatment-related adverse events were slightly increased in the combination arm (83.7% vs 72.4%)—mostly pruritus, fatigue, and rash—but grade 3 and 4 toxicities were limited (21.1% vs 11.1%). There were four treatment-related deaths in the combination arm and two in the nivolumab arm.

Immune-mediated adverse events were slightly more frequent with the combination (18.6% vs 14.8%)—mostly thyroid abnormalities, rash, and diarrhea/colitis. Importantly, myocarditis occurred in six (1.7%) patients treated with nivolumab/relatlimab and two (0.6%) treated with nivolumab. Troponin monitoring was done for the first 2 months of treatment, per protocol.

The study’s invited discussant, Adil Daud, MBBS, Co-Director of the University of California, San Francisco (UCSF) Melanoma Center and Director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center, said the findings of RELATIVITY-047 “mark a major advance for immunotherapy beyond CTLA-4 and PD-1.”

Disclosure: For full disclosures of the study authors, visit coi.asco.org.