Relatlimab/Nivolumab Combo Continues to Impress in Previously Untreated Metastatic or Unresectable Melanoma


The fixed-dose combination of relatlimab and nivolumab continued to demonstrate a consistent progression-free survival benefit, showcased a clinically meaningful improvement in overall survival, and elicited a higher objective response rate than nivolumab alone in previously untreated patients with metastatic or unresectable melanoma.

Georgina Long, AO, BSc, PhD, MBBS, FRACP, FAHMS

Georgina Long, AO, BSc, PhD, MBBS, FRACP, FAHMS

The fixed-dose combination of relatlimab and nivolumab (Opdivo) continued to demonstrate a consistent progression-free survival (PFS) benefit, showcased a clinically meaningful improvement in overall survival (OS), and elicited a higher objective response rate (ORR) than nivolumab alone in previously untreated patients with metastatic or unresectable melanoma, according to additional data from the phase 2/3 RELATIVITY-047 trial (NCT03470922) presented during the March 2022 ASCO Plenary Series.1

At a median follow-up of 19.3 months, the doublet (n = 355) resulted in a median PFS of 10.22 months (95% CI, 6.51-14.75) per blinded independent central review (BICR) vs 4.63 months (95% CI, 3.48-6.44) with single-agent nivolumab (n = 359), translating to a 22% reduction in the risk of disease progression or death in this population (HR, 0.78; 95% CI, 0.64-0.94).

The median OS with relatlimab plus nivolumab had not yet been reached (NR; 95% CI, 43.20-NR) vs 34.10 (95% CI, 25.32-NR) with nivolumab alone (HR, 0.80; 95% CI, 0.64-1.01; P = .0593). Although this benefit was not found to be statistically significant, it was determined to be clinically meaningful.

Notably, OS rates were higher in the investigative and control arms at 12 months, with rates of 77.0% (95% CI, 72.2%-81.1%) and 71.6% (95% CI, 66.6%-76.0%), respectively, as well as at 24 months, with rates of 63.7% (95% CI, 58.1%-68.7%) and 58.3% (95% CI, 52.7%-63.4%), respectively. At 36 months, this trend continued, with rates of 55.8% (95% CI, 49.8%-61.4%) and 48.8% (95% CI, 42.7%-54.7%) in the investigative and control arms, respectively.

Moreover, the addition of relatlimab to nivolumab resulted in an improved ORR of 43.1% (95% CI, 37.9%-48.4%) vs 32.6% (95% CI, 27.8%-37.7%) with nivolumab alone (odds ratio, 1.6; 95% CI, 1.2-2.2).

“Nivolumab plus relatlimab had a manageable safety profile, with no new or unexpected safety signals,” lead study author Georgina Long, AO, BSc, PhD, MBBS, FRACP, FAHMS, of The University of Sydney, Royal North Shore, and Mater Hospitals, said during the presentation on the data. “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.”

Although immune checkpoint inhibitors have revolutionized treatment for patients with advanced disease, new combination regimens are needed to improve risk-benefit profiles. A human LAG-3–blocking antibody, relatlimab restores the effector function of exhausted T cells in this population.

In September 2021, the FDA granted a priority review to a biologics license application seeking the approval of relatlimab plus nivolumab in adult and pediatric patients who are aged 12 years and older, weigh at least 40 kg, and who have unresectable or metastatic melanoma.2 The application is supported by earlier findings from RELATIVITY-047, which were presented during the 2021 ASCO Annual Meeting. At a median follow-up of 13.2 months, the doublet more than doubled the median PFS vs nivolumab monotherapy in these patients, at 10.12 months (95% CI, 6.37-15.74) vs 4.63 months (95% CI, 3.38-5.62), respectively (HR, 0.75; 95% CI, 0.62-0.92; P = .0055).3

Under the Prescription Drug User Fee Act, the regulatory agency is slated to decide on the application by March 19, 2022.

RELATIVITY-047 enrolled patients with previously untreated, unresectable, or metastatic melanoma who had an ECOG performance status of 0 or 1. A total of 714 study participants were randomized 1:1 to receive the fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg given every 4 weeks vs nivolumab alone at the same dose and schedule.

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.

The primary end point of the trial was PFS per BICR, and key secondary end points comprised OS and ORR per BICR. End points were tested in hierarchy, with PFS evaluated first, followed by OS, and then ORR.

Baseline characteristics were noted to be well balanced between the 2 treatment arms. In the total population, the median age was 63 years, 41.7% were female, and 66.9% had an ECOG performance status of 0. The serum lactate dehydrogenase level was above the upper limit of normal in 36.1% of patients.

Moreover, LAG-3 expression was 1% or higher in 75.2% of patients, and it was lower than 1% in 24.8% of patients. PD-L1 expression was at least 1% in 41.0% of patients, and lower than 1% in 59.0% of patients. Additionally, 38.5% of patients had BRAF-mutated disease, and 61.5% had BRAF wild-type disease. Lastly, 65.7% of patients had AJCC M stage of M0/M1any[0], and 34.3% had M1any[1].

Additional data showed that PFS rates continued to be higher in the relatlimab/nivolumab arm vs the nivolumab-alone arm. At 12 months, these rates were 48.0% (95% CI, 42.5%-53.4%) and 36.9% (95% CI, 31.7%-42.1%), respectively, and at 24 months, these rates were 38.5% (95% CI, 32.7%-44.2%) and 29.0% (95% CI, 23.8%-34.4%), respectively.

Notably, PFS and OS benefit favored the combination over the monotherapy across all stratification factors analyzed.

In the investigative arm, the complete response rate was 16.3%, the partial response rate was 26.8%, and 17.2% of patients achieved stable disease. Additionally, 29.6% of patients experienced disease progression.

The median duration of response had not yet been reached in both the investigative (95% CI, 29.57-NR) and control (95% CI, 29.93-NR) arms. The disease control rate achieved with relatlimab/nivolumab was 62.8% (95% CI, 57.6%-67.9%) vs 50.7% (95% CI, 45.4%-56.0%) with nivolumab alone.

Fewer patients who received the combination went on to receive subsequent therapy vs those who received the monotherapy, at 40.8% and 42.6%, respectively. Moreover, fewer patients in the investigative arm received systemic therapy vs those in the control arm, at 32.7% vs 34.5%, respectively. Additionally, 11.8% of patients who received relatlimab/nivolumab went on to receive PD-L1 and/or CTLA-4 inhibitors vs 15.9% of those who were given nivolumab alone.

Specifically, 4.2% of patients on the combination arm received nivolumab and ipilimumab (Yervoy), 4.2% received single-agent nivolumab, 3.7% received single-agent ipilimumab, 1.7% received pembrolizumab (Keytruda) monotherapy, and no patients received single-agent avelumab (Bavencio); these rates were 6.7%, 5.6%, 5.3%, 2.8%, and 0.3%, respectively.

Additionally, 12.4% of patients on the investigative arm went on to receive BRAF and/or MEK inhibitors vs 14.8% of those on the control arm. Other subsequent treatment was received by 13.8% of those who received the doublet vs 12.3% of those who were given the monotherapy. Slightly more patients on the investigative arm received radiotherapy at 14.6% vs 12.3% on the control arm; however, more patients on the control arm underwent surgery, at 8.1% vs 7.0%, respectively.

Any-grade adverse effects (AEs) occurred in 99.2% of those who received relatlimab/nivolumab (n = 355) vs 95.8% of those who were given nivolumab alone (n = 359); these effects were grade 3 or 4 in severity in 43.4% and 35.1% of patients, respectively. Any-grade treatment-related AEs (TRAEs) were experienced by 83.7% of those on the investigative arm and 72.4% of those on the control arm; grade 3 or 4 TRAEs occurred in 21.1% and 11.1% of patients, respectively. Grade 3 or 4 TRAEs resulted in treatment discontinuation in 9.0% of those who received the doublet and 3.6% of those who were given the monotherapy.

The most common TRAEs that occurred in 10% or more of patients who received relatlimab plus nivolumab were pruritus (any grade, 24.5%), fatigue (any grade, 23.4%; grade 3/4, 1.4%), rash (any grade, 16.6%; grade 3/4, 0.8%), hypothyroidism (any grade, 15.5%), arthralgia (any grade, 14.9%; grade 3/4, 0.8%), diarrhea (any grade, 14.9%; grade 3/4, 1.1%), and vitiligo (any grade, 12.7%).

Treatment-related deaths occurred in 4 patients in the investigative arm and 2 patients in the control arm.

The most common immune-mediated AEs of any grade in the doublet arm were hypothyroidism/thyroiditis (18.6%), rash (11.0%), and diarrhea/colitis (7.0%). The most frequently experienced grade 3 or 4 immune-mediated toxicities in this arm were hepatitis (4.2%), adrenal insufficiency (1.7%), and diarrhea/colitis (1.4%).

An additional toxicity of interest was any-grade myocarditis, which was observed in 6 patients on the investigative arm and 2 patients on the control arm. Troponin monitoring was done for the first 2 months of treatment in accordance with the trial protocol.


  1. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab vs nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047). J Clin Oncol. 2022;40(suppl 36):360385. doi:10.1200/JCO.2022.40.36_suppl.360385
  2. US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for LAG-3-blocking antibody relatlimab and nivolumab fixed-dose combination as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb; September 20, 2021. Accessed March 15, 2021.
  3. Lipson EJ, Tawbi HA, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-046 (CA224-047). J Clin Oncol. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503
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