Addition of Relatlimab to Nivolumab Yields Longer TFI and Improved PFS2 in Metastatic or Unresectable Melanoma


Patients with previously untreated metastatic or unresectable melanoma achieved promising benefit following treatment with relatlimab/nivolumab combination therapy.

The combination of relatlimab and nivolumab (Opdivo) led to a longer treatment-free interval (TFI) as well as a reduction in risk of progression or death following the next line of therapy vs nivolumab alone in patients with previously untreated metastatic or unresectable melanoma, according to findings from the phase 2/3 RELATIVITY-047 trial (NCT03470922), which were presented during the 2021 European Society for Medical Oncology Congress.1

The new efficacy results demonstrated that those who received the doublet and discontinued treatment (n = 167) experienced a longer TFI vs single-agent nivolumab (n = 151), with a median TFI of 3.22 (range, 0.1-30.4) vs 1.41 (range, 0.1-25.6), respectively.

Relatlimab plus nivolumab also reduced the risk of progression following the next line of systemic therapy (PFS2), per investigator assessment, or death compared with nivolumab alone. The median PFS2 in the investigative arm had not yet been reached (95% CI, 21.75–not reached) vs 20.04 months (95% CI, 15.44-25.13) with nivolumab alone (hazard ratio [HR], 0.77; 95% CI, 0.61-0.97).

“Patients on relatlimab/nivolumab experienced prolonged benefit beyond initial treatment and first progression. Among those who discontinued study therapy, those treated with relatlimab/nivolumab had a long TFI vs nivolumab alone,” F. Stephen Hodi, MD, lead study author, director of the Melanoma Center, director of the Center for Immuno-Oncology, and Sharon Crowley Martin Chair for Melanoma at Dana-Farber Cancer Institute, said in a presentation on the data. “A greater proportion of patients treated with relatlimab/nivolumab remained without subsequent systemic therapy and [the combination] reduced the risk of progression after the next line of systemic therapy, per investigator assessment, or death vs nivolumab alone.”

It is known that LAG-3 and PD-1 are distinct immune checkpoints, but they are often co-expressed on tumor infiltrating lymphocytes and are known to play a role in tumor-mediated T-cell exhaustion, according to Hodi, who is also a professor of medicine at Harvard Medical school.

Relatlimab is a human LAG-3–blocking antibody that was designed to restore the effector function of T cells that have been exhausted.

RELATIVITY-047 is the first global randomized, double-blind, phase 2/3 registrational study to evaluate the combination of LAG-3 and PD-1 inhibition with relatlimab and nivolumab as a novel fixed-dose combination vs nivolumab alone in patients with previously untreated metastatic or unresectable melanoma.

To be eligible for enrollment, patients needed to have previously untreated metastatic or unresectable melanoma and an ECOG performance status of 0 or 1.

A total of 714 patients were enrolled to the trial, and were randomized 1:1 to receive either the fixed-dose combination of relatlimab at 160 mg plus nivolumab at 480 mg every 4 weeks (n = 355) or nivolumab alone at 480 mg every 4 weeks (n = 359).

Participants were stratified based on LAG-3 and PD-1 expression status, BRAF mutational status, and American Joint Committee on Cancer version 8 metastatic stage.

The primary end point of the trial was progression-free survival (PFS) by blinded independent central review (BICR), and key secondary end points included overall survival and objective response rate by BICR. Exploratory end points of interest included TFI and PFS2.

Data from RELATIVITY-047 previously reported at the 2021 ASCO Annual Meeting showed that the doublet resulted in a median PFS of 10.12 months (95% CI, 6.37-15.74) vs 4.63 months (95% CI, 3.38-5.62) with nivolumab alone (HR, 0.75; 95% CI, 0.62-0.92; P = .0055).2 The 12-month PFS rates in the investigative and control arms were 47.7% (95% CI, 41.8%-53.2%) and 36.0% (95% CI, 30.5%-41.6%), respectively.

“The PFS benefit was seen at the time of the first scan, which was 12 weeks, and continued thereafter,” Hodi noted. “Relatlimab plus nivolumab demonstrated superior PFS, with more than a doubling of improvement compared with nivolumab alone. We also consistently saw the PFS benefit [of the combination] across key subgroups, including [disease] subtypes such as acral and mucosal melanoma.”

The HR for PFS for cutaneous acral melanoma was 0.84 (95% CI, 0.50-1.39), 0.73 (95% CI, 0.57-0.93) for cutaneous non-acral disease, 0.72 (95% CI, 0.36-1.45) for mucosal disease, and 0.77 (95% CI, 0.44-1.36) for other subtypes.

During the 2021 ESMO Congress, Hodi shared data on the exploratory end points TFI and PFS2. TFI was defined as the time from the end of study therapy to subsequent systemic treatment or last known alive date in patients who discontinued study therapy; this excluded those who died before receiving subsequent systemic therapy. Investigators defined PFS2 as the time from randomization to progression following the next line of systemic therapy, per investigator assessment, or death.

The median duration of treatment with relatlimab/nivolumab was 5.6 months (minimum, 0.0; maximum, 31.5) vs 4.9 months (minimum, 0.0; maximum, 32.2) with nivolumab alone. Slightly more patients on the investigative arm discontinued treatment vs those on the control arm, at 66.8% and 64.9%, respectively.

The most common reason for discontinuation on the doublet and monotherapy arms was progressive disease (36.3% vs 46.0%, respectively), followed by treatment-related toxicity (17.7% vs 8.9%), patient request (5.4% vs 3.3%), and an adverse effect (AE) that was not related to treatment (3.4% vs 3.9%).

More patients on the nivolumab-alone arm received subsequent therapy compared with the relatlimab/nivolumab arm, at 37.3% vs 35.5%, respectively; 29.8% vs 27.9% of patients, respectively, received systemic therapy.

Subsequent treatments received in the investigative and control arms included PD-1 and/or CTLA-4 inhibitors (9.0% vs 12.8%, respectively), BRAF and/or MEK inhibitors (11.5% vs 13.9%), or other systemic options (10.7% vs 12.3%). Moreover, 11.5% of those on the investigative arm vs 10.0% of those on the control arm went on to receive radiotherapy; 5.1% vs 7.2% of patients, respectively, went on to receive surgery.

Among the off-treatment patients included in the TFI analysis, 40.7% of those who received relatlimab/nivolumab did not receive subsequent systemic therapy vs 29.1% of those who received single-agent nivolumab. In the investigative and control arms, 31.1% and 37.7% of patients, respectively, went on to receive subsequent treatment.

“This analysis included patients who were alive and off therapy or who died following subsequent systemic therapy,” Hodi said. “Of note, more patients on the relatlimab/nivolumab arm who discontinued study treatment did not receive subsequent therapy at the time of this analysis as compared with nivolumab alone.”

Regarding PFS2, the separation between the curves was seen at about 6 months and continued, according to Hodi, indicating the potential benefits of the combination regimen beyond initial treatment.

Relatlimab plus nivolumab was found to have a manageable toxicity profile and did not showcase any unexpected safety signals. Any-grade AEs were reported in 97.2% of those on the investigative arm vs 94.4% of those on the control arm; 40.3% and 33.4% of patients, respectively, reported grade 3 or 4 AEs.

Treatment-related AEs (TRAEs) were reported by 81.1% of those who received the doublet vs 69.9% of those who were given the monotherapy; grade 3 or 4 TRAEs were experienced by 18.9% and 9.7% of patients, respectively. Any-grade TRAEs resulted in discontinuation in 14.6% and 6.7% of those on relatlimab/nivolumab and nivolumab monotherapy, respectively. Grade 3 or 4 TRAEs led to discontinuation in 8.5% of those on the investigative arm vs 3.1% of those on the control arm.

Five treatment-related deaths occurred: 3 in the combination arm (includes hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis) and 2 in the monotherapy arm (includes sepsis and myocarditis and worsening pneumonia).


  1. Hodi FS, Tawbi HA, Lipson EJ, et al. Relatlimab (RELA) + nivolumab (NIVO) versus NIVO in previously untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 1036O.
  2. 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-047 (CA224-047). J Clin Oncol. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503
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