Research & Development
Bristol Myers Squibb Receives European Commission Approval for LAG-3-Blocking Antibody Combination, Opdualag, for the Treatment of Unresectable or Metastatic Melanoma with Tumor Cell PD-L1 Expression < 1%
16 September 2022 - - The European Commission has approved the fixed-dose combination of Opdualag (nivolumab and relatlimab) for the first-line treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older with tumor cell PD-L1 expression < 1%, US-based pharmaceutical company Bristol Myers Squibb (NYSE: BMY) said.

The EC's decision is based upon an exploratory analysis of results from the Phase 2/3 RELATIVITY-047 trial in patients with tumor cell expression < 1%, which demonstrated that treatment with the fixed-dose combination of the PD-1 inhibitor nivolumab and novel LAG-3-blocking antibody relatlimab more than doubled the median progression-free survival compared to nivolumab monotherapy an established standard of care.

No new safety events were identified with the combination when compared to nivolumab monotherapy.

The EC decision allows for the use of Opdualag for the first-line treatment of adults and adolescents 12 years of age and older with advanced melanoma and tumor cell PD-L1 expression < 1% in all European Union member states, as well as Iceland, Liechtenstein, and Norway.

The indication in the European Union is based upon an exploratory analysis of the RELATIVITY-047 data in patients with tumor cell PD-L1 expression < 1%:

Median PFS was 6.7 months in patients receiving Opdualag (95% Confidence Interval [CI]: 4.7 to 12.0); (Hazard Ratio [HR] 0.68 (0.53, 0.86)) compared to 3.0 months in patients receiving nivolumab monotherapy (95% CI:2.8 to 4.5).

Median overall survival in the Opdualag arm of the trial has not yet been reached (HR 0.78 (0.59, 1.04)).

The most common adverse reactions were fatigue, musculoskeletal pain, rash, arthralgia, diarrhea, pruritus, headache, nausea, cough, decreased appetite, hypothyroidism, abdominal pain, vitiligo, pyrexia, constipation, urinary tract infection, dyspnea, and vomiting.

The most common serious adverse reactions were adrenal insufficiency, anemia, back pain, colitis, diarrhea, myocarditis, pneumonia, and urinary tract infection.

The incidence of Grade 3-5 adverse reactions was 43% among patients treated with Opdualag compared to 35% among patients receiving nivolumab monotherapy.

The RELATIVITY-047 trial also met its primary endpoint of PFS in the all-comer population.
Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland, Wales).

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.

Patients were enrolled regardless of tumor cell PD-L1 expression. 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 determined by Blinded Independent Central Review using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in the all-comer population.

The secondary endpoints are overall survival and objective response rate in the all-comer population.

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, unacceptable toxicity or withdrawal of consent.

Lymphocyte-activation gene 3 (LAG-3) is a cell-surface molecule expressed on effector T cells and regulatory T cells (Tregs) and functions to control T-cell response, activation and growth.

Preclinical studies indicate that inhibition of LAG-3 may restore effector function of exhausted T cells and potentially promote an anti-tumor response.

Early research demonstrates that targeting LAG-3 in combination with other potentially complementary immune checkpoints may be a key strategy to more effectively potentiate anti-tumor immune activity.

Bristol Myers Squibb is evaluating relatlimab, its LAG-3-blocking antibody, in clinical trials in combination with other agents in a variety of tumor types.

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. The incidence of melanoma has been increasing steadily for the last 30 years.

In the United States, 106,110 new diagnoses of melanoma and about 7,180 related deaths are estimated for 2021.

Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths.

Melanoma can be mostly treatable when caught in its very early stages; however, survival rates can decrease as the disease progresses.

Bristol Myers Squibb is inspired by a single vision -- transforming patients' lives through science. The goal of the company's cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility.

Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus.

Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient's life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

Opdualag (nivolumab and relatlimab-rmbw) is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.
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