U.S. Food and Drug Administration Approves First LAG-3-Blocking Antibody Combination, Opdualag™ (nivolumab and relatlimab-rmbw), as Treatment for Patients with Unresectable or Metastatic Melanoma

Opdualag, a first-in-class, fixed-dose dual immunotherapy combination treatment of the PD-1 inhibitor nivolumab and novel LAG-3-blocking antibody relatlimab, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

Relatlimab is the third immune checkpoint inhibitor from Bristol Myers Squibb, adding to the Company’s growing and differentiated oncology portfolio.

Bristol Myers Squibb said that Opdulag (nivolumab and relatlimab-rmbw), a new, first-in-class, fixed-dose combination of nivolumab and relatlimab, administered as a single intravenous infusion, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. The approval is based on the Phase 2/3 RELATIVITY-047 trial, which compared Opdualag (n=355) to nivolumab alone (n=359), BMS said.

BMS said the trial met its primary endpoint, progression-free survival (PFS), and Opdualag more than doubled the median PFS when compared to nivolumab monotherapy, 10.1 months (95% Confidence Interval [CI]: 6.4 to 15.7) versus 4.6 months. The Opdualag safety profile was similar to that previously reported for nivolumab. No new safety events were identified with the combination when compared to nivolumab monotherapy. Grade 3/4 drug-related adverse events were 18.9% in the Opdualag arm compared to 9.7% in the nivolumab arm. Drug-related adverse events leading to discontinuation were 14.6% in the Opdualag arm compared to 6.7% in the nivolumab arm.

“Since the approval of the first immune checkpoint inhibitor more than 10 years ago, we’ve seen immunotherapy, alone and in combination, revolutionize the treatment of patients with advanced melanoma,” said F. Stephen Hodi, M.D., director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute. “Today’s approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve anti-tumor response by targeting two different immune checkpoints — LAG-3 and PD-1.”

Opdualag is associated with the following Warnings & Precautions: severe and fatal immune-mediated adverse reactions (IMARs) including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); and embryo-fetal toxicity.

“While we have made great progress in the treatment of advanced melanoma over the past decade, we are committed to expanding dual immunotherapy treatment options for these patients,” said Samit Hirawat, chief medical officer, global drug development, Bristol Myers Squibb. “Inhibiting LAG-3 with relatlimab, in a fixed-dose combination with nivolumab, represents a new treatment approach that builds on our legacy of bringing innovative immunotherapy options to patients. The approval of a new medicine that includes our third distinct checkpoint inhibitor marks an important step forward in giving patients more options beyond monotherapy treatment.”

Lymphocyte activation gene-3 (LAG-3) and programmed death-1 (PD-1) are two distinct inhibitory immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes, thus contributing to tumor-mediated T-cell exhaustion. The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone. Relatlimab (in combination with nivolumab) is the first LAG-3-blocking antibody to demonstrate a benefit in a Phase 3 study. It is the third checkpoint inhibitor (along with anti-PD-1 and anti-CTLA-4) for Bristol Myers Squibb.

“Today’s approval is exciting news and offers new hope to the melanoma community. The availability of this treatment combination may enable patients to potentially benefit from a new, first-in-class dual immunotherapy,” said Michael Kaplan, president and CEO, Melanoma Research Alliance.

The FDA-approved dosing for adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every four weeks. The recommended dosage for pediatric patients 12 years of age or older who weigh less than 40 kg, and pediatric patients younger than 12 years of age, has not been established.

This application was approved under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible. The review was also conducted under the FDA’s Project Orbis initiative, which enabled concurrent review by the health authorities in Australia, Brazil and Switzerland, where the application remains under review.

About RELATIVITY-047

RELATIVITY-047 is a global, randomized, double-blind Phase 2/3 study evaluating the fixed-dose combination of nivolumab and relatlimab versus nivolumab alone in patients with previously untreated metastatic or unresectable melanoma. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases. The primary endpoint of the trial is progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The secondary endpoints are overall survival (OS) and objective response rate (ORR). A total of 714 patients were randomized 1:1 to receive a fixed-dose combination of nivolumab (480 mg) and relatlimab (160 mg) or nivolumab (480 mg) by intravenous infusion every four weeks until disease progression or unacceptable toxicity.

Select Safety Profile From RELATIVITY-047

Adverse reactions leading to permanent discontinuation of Opdualag occurred in 18% of patients. Opdualag was interrupted due to an adverse reaction in 43% of patients.  Serious adverse reactions occurred in 36% of patients treated with Opdualag. The most frequent (≥1%) serious adverse reactions were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%). Fatal adverse reactions occurred in three (0.8%) patients treated with Opdualag and included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. The most common (≥20%) adverse reactions were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%). The Opdualag safety profile was similar to that previously reported for nivolumab. No new safety events were identified with the combination when compared to nivolumab monotherapy. Grade 3/4 drug-related adverse events were 18.9% in the Opdualag arm compared to 9.7% in the nivolumab arm. Drug-related adverse events leading to discontinuation were 14.6% in the Opdualag arm compared to 6.7% in the nivolumab arm.

About Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs.^5,6 The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, approximately 99,780 new diagnoses of melanoma and about 7,650 related deaths are estimated for 2022. Melanoma can be mostly treatable when caught in its very early stages; however, survival rates can decrease as the disease progresses.