FDA grants priority review for fixed-dose relatlimab plus nivolumab based on RELATIVITY-047

The U.S Food and Drug Administration (FDA) has granted priority review for the fixed-dose combination of relatlimab, a LAG-3 targeting antibody, plus nivolumab based on the findings from RELATIVITY-047 (NCT03470922).1

Lymphocyte-activation gene 3 (LAG-3) is upregulated in melanoma and contributes to T-cell exhaustion. Blocking LAG-3 has been shown to restore T-cell effector function.2 Similarly, blockade of programmed cell death protein 1 (PD-1), which also inhibits T-cell activity, can restore effector function.3 Relatlimab and nivolumab are human monoclonal antibodies targeting LAG-3 and PD-1 respectively. RELATIVITY-0474 is a randomized Phase II/III trial evaluating the novel checkpoint inhibitor combination of relatlimab + nivolumab versus nivolumab monotherapy in first-line advanced melanoma, to evaluate whether relatlimab and nivolumab act synergistically to enhance antitumor immune responses. The primary endpoint was progression-free survival (PFS). Patients (n = 714) were randomized to receive either relatlimab + nivolumab as a fixed-dose combination (FDC) or nivolumab monotherapy.

Initial results were presented by Evan J. Lipson, MD, John Hopkins Medical Institute, Baltimore, MD at the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting. Median PFS of patients receiving the combination of relatlimab + nivolumab was statistically significantly higher at 10.1 months [95% CI, 6.4–15.7], compared with 4.6 months [95% CI, 3.4–5.6] in the nivolumab monotherapy group. The hazard ratio was 0.75 [95% CI, 0.6–0.9]; P = 0.0055).

The incidence of grade 3/4 toxicities was higher in the relatlimab plus nivolumab group (18.9%) than in the nivolumab monotherapy group (9.7%). Treatment-related adverse events (TRAEs) that led to discontinuation of treatment occurred in 14.6% of patients receiving relatlimab + nivolumab compared with only 6.7% of nivolumab patients. However, these adverse events did not appear to represent new safety signals and occurred at a lower rate than that observed in other combination immunotherapy studies.5 Secondary endpoints included overall survival and objective response rate, of which outcomes are still being assessed.

“This is the first Phase III study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy, not just for melanoma patients, but for patients with cancer generally, and I think this establishes the LAG-3 pathway as the third immune checkpoint pathway, really in history, after the CTLA-4 and PD-1 pathways for which a blockade has clinically benefited”

Presenting author of the RELATIVITY-047 study, Evan J. Lipson, MD, of the John Hopkins Medical Institute, Baltimore, MD

In summary, the primary endpoint of RELATIVITY-047 was met, suggesting relatlimab + nivolumab is a potential novel combination immunotherapy treatment option for patients with previously untreated unresectable or metastatic melanoma. Despite the combination immunotherapy having a higher toxicity rate, the safety profile is deemed manageable. The trial also validates inhibition of the LAG-3 pathway as clinically beneficial for cancer treatment.


  1. 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 January 13, 2022. https://bit.ly/3tVGyYG
  2. Maruhashi T, Sugiura D, Okazaki I, et al. LAG-3: from molecular functions to clinical applications. Journal for ImmunoTherapy of Cancer2020 Sep 13;8:e001014
  3. Rausch MP, Hastings KT. Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application. In: Ward WH, Farma JM, editors. Cutaneous Melanoma: Etiology and Therapy. Brisbane (AU): Codon Publications; 2017 Dec 21. Chapter 9.
  4. Lipson EJ, Tawbi H A-H, 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). JCO. 2021 May 20;39(15_suppl):9503-9503
  5. Simeone E, Grimaldi AM, Festino L et al. Immunotherapy in metastatic melanoma: a novel scenario of new toxicities and their management. Melanoma Manag. 2019 Dec;6(4):MMT30.