PD-1/LAG-3 Dual Blockade: Relatlimab + Opdivo Shows Superior Efficacy Over Opdivo Monotherapy in First-Line Unresectable or Metastatic Melanoma, Under Regulatory Review in U.S. and Europe

Melanoma(Image source: healthjade.com)

October 12, 2021 /BioonBIOON/ -- Bristol-Myers Squibb (BMS) recently announced that the U.S. Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) for a fixed-dose combination of the LAG-3-blocking antibody relatlimab and the PD-1-blocking antibody Opdivo (generic name: nivolumab) and has granted Priority Review. Additionally, the European Medicines Agency (EMA) has also accepted the Marketing Authorization Application (MAA) for the fixed-dose combination of relatlimab and Opdivo. The BLA and MAA seek approval forRelatlimab and Opdivo Fixed-Dose Combination: Administered as a single infusion for the treatment of unresectable or metastatic melanoma in adult and pediatric patients (aged ≥12 years and weighing ≥40 kg). In the United States, the FDA has designated March 19, 2022, as the Prescription Drug User Fee Act (PDUFA) target date.

Both this BLA and MAA are based on the results of the Phase 2/3 RELATIVITY-047 (CA224-047) trial. This is a randomized, double-blind Phase 2/3 study in patients with previously untreated metastatic or unresectableMelanomaconducted in patients, evaluating the efficacy and safety of a fixed-dose combination of relatlimab and Opdivo versus standard-of-care Opdivo monotherapy for first-line treatment. The results showed that,Compared with standard-of-care Opdivo monotherapy, first-line treatment with the fixed-dose combination of relatlimab plus Opdivo demonstrated robust efficacy, significantly prolonging progression-free survival (PFS), with differences that were both statistically and clinically significant.

Relatlimab is the third distinct checkpoint inhibitor being evaluated by Bristol-Myers Squibb (anti-PD-1, anti-CTLA-4, anti-LAG-3). Data from the Phase 2/3 RELATIVITY-047 trial were released in May of this year, evaluating an anti-LAG-3 antibody.Clinical Trialfirst Phase 3 data. Meanwhile,Relatlimab (in combination with Opdivo) is the first LAG-3-blocking antibody demonstrated to benefit patients in a Phase 3 study.

Lymphocyte-activation gene 3 (LAG-3, CD223) is a cell surface molecule expressed on effector T cells and regulatory T cells (Tregs). LAG-3 regulates an inhibitory immune checkpoint pathway, limiting T cell activity and leading to attackTumorCellular function is impaired. In chronic diseases such as cancer, T cells exhibit progressive exhaustion, characterized by the upregulation of inhibitory immune checkpoints such as PD-1 and LAG-3. Although LAG-3 and PD-1 represent distinct immune checkpoint pathways, they may act synergistically on effector T cells, leading to T cell exhaustion.

Relatlimab Mechanism of Action (Click image to enlarge)

In the RELATIVITY-047 trial, a total of 741 patients were randomized in a 1:1 ratio to receive a fixed-dose combination of relatlimab and Opdivo (relatlimab 160 mg and Opdivo 400 mg administered via intravenous infusion every 4 weeks) or Opdivo monotherapy (480 mg administered via intravenous infusion every 4 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR), and the secondary endpoints were overall survival (OS) and objective response rate (ORR).

The results showed that the study met the primary PFS endpoint. Notably,The relatlimab + Opdivo regimen is the first to be proven, compared with anti-PD-1 monotherapy, in the treatment of metastaticMelanomaa regimen demonstrating a statistical advantage in this aspect.

Compared with the Opdivo treatment group, the relatlimab plus Opdivo treatment group demonstrated a statistically and clinically significant improvement (median PFS: 10.12 months vs 4.64 months), with a 25% reduction in the risk of disease progression or death (HR=0.75, 95% CI: 0.62-0.92; p=0.0055). The PFS benefit of the fixed-dose combination (relatlimab plus Opdivo) was observed as early as the first scan and remained consistent over time. In exploratory, descriptive analyses, the relatlimab plus Opdivo combination prolonged PFS across all prespecified subgroups and stratification factors.

In this study, the safety profile of the relatlimab plus Opdivo fixed-dose combination was manageable and consistent with previously reported safety data for relatlimab and Opdivo. Compared with Opdivo monotherapy, no new safety signals or new types of clinically important events were identified with the fixed-dose combination therapy. The incidence of grade 3/4 treatment-related adverse events was 18.9% in the combination group versus 9.7% in the Opdivo group. Treatment-related adverse events leading to discontinuation occurred in 14.6% of the combination group compared with 6.7% in the Opdivo group.

Immune checkpoint inhibitors used alone or in combination have transformed metastatic or unresectable`Melanoma`treatment approaches for patients, improving survival rates. However, a substantial number of patients may still benefit from a novel combination therapy that leverages potentially complementary pathways to enhance anti-TumorActivity. The results of the RELATIVITY-047 study showed that,Targeting the LAG-3 pathway in combination with PD-1 inhibition may be a key strategy to enhance the immune response and help improve the prognosis of these patients.

LAG-3 represents a novel immunotherapy target., the RELATIVITY-047 study demonstrated the significant benefit of the novel combination regimen of relatlimab and Opdivo for the simultaneous inhibition of LAG-3 and PD-1. Based on the observed efficacy and safety, the potential of combining Opdivo and relatlimab in metastaticMelanomaprovides an important new treatment option for patients.

Senior Vice President, Bristol-Myers Squibb andTumorHead of Development Jonathan Cheng: "Despite the significant progress we have made in melanoma treatment since the introduction of immune checkpoint inhibitors, there are still patients who can benefit from novel dual immunotherapy approaches. Based on the results of the RELATIVITY-047 trial, we believe the fixed-dose combination of relatlimab and Opdivo has the potential to improve outcomes for metastatic or unresectable"Melanomapatient prognosis. Relatlimab is Bristol-Myers Squibb's third novel checkpoint inhibitor, and we look forward to introducing the first LAG-3 blocking antibody to help patients.” (Bioon.com)

Source:U.S. 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