FDA Grants Priority Review to Relatlimab/Nivolumab for Unresectable or Metastatic Melanoma


The FDA has granted priority review to a biologics license application for the fixed-dose combination of relatlimab plus nivolumab for the treatment of adult and pediatric patients aged 12 years and older and weighing at least 40 kg who have unresectable or metastatic melanoma.

The FDA has granted priority review to a biologics license application (BLA) for the fixed-dose combination of relatlimab plus nivolumab (Opdivo) for the treatment of adult and pediatric patients aged 12 years and older and weighing at least 40 kg who have unresectable or metastatic melanoma.1

The application is supported by data yielded from the phase 2/3 RELATIVITY-047 trial (NCT03470922), which demonstrated that the doublet more than doubled median progression-free survival (PFS) per blinded independent central review (BICR) vs nivolumab alone when used as frontline treatment in patients with advanced melanoma.2

Primary results presented during the 2021 ASCO Annual Meeting demonstrated a median PFS of 10.12 months (95% CI, 6.37-15.74) in the investigative arm vs 4.63 months (95% CI, 3.38-5.62) in the control arm (HR, 0.75; 95% CI, 0.62-0.92; P = .0055). The 12-month PFS rate with relatlimab plus nivolumab was 47.7% (95% CI, 41.8%-53.2%) vs 36.0% (95% CI, 30.5%-41.6%) with nivolumab alone.

Notably, the PFS benefit achieved with the doublet was observed irrespective of prespecified subgroups and stratification factors.

The regulatory agency is expected to decide on the BLA by March 19, 2022, under the Prescription Drug User Fee Act.

“Although we’ve seen significant advances in the treatment of melanoma since the introduction of immune checkpoint inhibitors, there continue to be patients who could benefit from a novel dual immunotherapy approach,” Jonathan Cheng, senior vice president and head of oncology development at Bristol Myers Squibb, stated in a press release. “Based on the results of the RELATIVITY-047 trial, we believe that the relatlimab and nivolumab fixed-dose combination has the potential to improve outcomes for patients with metastatic or unresectable melanoma. We look forward to potentially introducing the first LAG-3–blocking antibody, and Bristol Myers Squibb’s third distinct checkpoint inhibitor, to help patients in need.”

The global, double-blind, phase 2/3 trial enrolled previously untreated patients with unresectable or metastatic melanoma who had an ECOG performance status of 0 or 1.

A total of 714 participants were randomized 1:1 to receive either the intravenous (IV) fixed-dose combination comprised of relatlimab at 160 mg plus nivolumab at 480 mg every 4 weeks or IV nivolumab at 480 mg every 4 weeks. Stratification factors included LAG-3 and PD-L1 status, BRAF mutational status, and American Joint Committee on Cancer (AJCC) version 8 metastatic stage.

The primary end point of the trial was PFS by BICR, and key secondary end points included overall survival (OS) and overall response rate (ORR) by BICR.

Across the arms, the median age of patients was 63 years, and 41.7% were female. Most patients (66.9%) had an ECOG performance status of 0, and 36.1% had a serum lactate dehydrogenase level that was greater than the upper limit of normal. Moreover, 38.9% of patients had a AJCC v.8 metastatic stage of M1C, and 2.4% had a stage of M1D.

Additionally, 8.4% of patients previously received neoadjuvant or adjuvant therapy. The median tumor burden in the investigative arm was 59.0 mm vs 54.5 mm in the control arm. Approximately 75% (75.2%) had a LAG-3 expression of 1% or higher, 59.0% had a PD-L1 expression less than 1%, 61.5% had BRAF wild-type disease, and 65.7% had a AJCC metastatic stage of M0/M1any(0).

Additional data showed that 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.

The PFS benefit favored the fixed-dose combination over nivolumab, regardless of LAG-3 expression status. Specifically, among those with a LAG-3 expression of 1% or higher who received relatlimab/nivolumab (n = 268) or nivolumab alone (n = 269), the median PFS was 12.58 months (95% CI, 6.67-23.10) and 4.76 months (95% CI, 4.47-8.61), respectively (HR, 0.75; 95% CI, 0.59-0.95). Among the subset of patients with a LAG-3 expression of less than 1%, the median PFS was 4.83 months (95% CI, 2.86-10.05) in those who received the doublet (n = 87) vs 2.79 months (95% CI, 2.79-4.63) in those who were given the monotherapy (n = 90; HR, 0.78; 95% CI, 0.54-1.15).

New efficacy results presented during the 2021 ESMO Congress showed that those who received relatlimab plus nivolumab and discontinued treatment (n = 167) had a longer treatment-free interval (TFI) than those given single-agent nivolumab (n = 151), with a median TFI of 3.32 months (range, 0.1-30.4) vs 1.41 months (range, 0.1-25.6), respectively.3

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

The median duration of treatment with relatlimab/nivolumab was 5.6 months vs 4.9 months 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 vs 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.

The combination was found to have a manageable safety profile and did not demonstrate any unexpected safety signals.

Follow-up for the secondary end points of OS and ORR is ongoing.


  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 September 20, 2021. https://bit.ly/3tVGyYG
  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-046 (CA224-047). J Clin Oncol. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503
  3. 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
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