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The FDA approved Bristol-Myers Squibb's (BMS) combination therapy Opdualag for the treatment of adults and children 12 years and older with unresectable or metastatic melanoma
.
The therapy consists of LAG-3 monoclonal antibody relatlimab and PD-1 monoclonal antibody nivolumab (Opdivo, nivolumab), and is the world's first LAG-3 antibody combination therapy to receive regulatory approval
So, compared with the already well-known predecessors PD-1 mAb and CTLA-4 mAb, is LAG-3 mAb a challenger or a helping partner?
Interrelationship in terms of mechanism of action
Interrelationship in terms of mechanism of action LAG-3 (CD223), the full name of Lymphocyte Activation Gene-3, was first discovered by Triebel and his team in 1990 when they screened a selective expression molecule of CD3-negative interleukin 2-dependent NK cells
.
LAG-3 is a type I transmembrane protein with four extracellular immunoglobulin-like domains (D1-D4).
LAG-3 and CD4 share a common ligand, MHC II (major histocompatibility complex II), due to the structural similarity of the extracellular domain
.
However, the D1 domain has a 30 amino acid loop, which gives LAG-3 a stronger affinity for MHCII
Figure 1.
Ligand interactions and structural similarity of LAG-3 and CD4
Source: doi:10.
1111/imr.
12519, Zhongkang Industrial Research Center
Compared with CD4, the D2-D4 domain of LAG-3 has multiple N-glycosylation sites, which are critical for binding to two other ligands, including LSECtin (hepatic sinusoidal endothelial cell lectin) on the surface of melanoma cells.
) and Galectin-3 (galectin-3) on the surface of somatic cells
.
Similar to PD-1 and CTLA-4, LAG-3 is not expressed on naive T cells, but can be induced to express on CD4+ and CD8+ T cells upon antigenic stimulation
.
In the tumor microenvironment, sustained antigen exposure leads to persistently high expression of LAG-3 and other inhibitory co-receptors such as PD-1 on CD4+ and CD8+ T cells, which in turn inhibits T cell activation and cytokine secretion
Significant synergistic effects of LAG-3 and PD-1 have been found in studies of multiple diseases, highlighting the potential uniqueness of LAG-3
.
Although PD-1 and CTLA-4 antibodies represent a major breakthrough in cancer treatment, only 10-30% of patients show long-term, durable responses
LAG-3 mAb R&D plan of BMS
LAG-3 mAb R&D plan of BMS At present, Yervoy (ipilimumab) of BMS is the only CTLA-4 inhibitor approved for marketing in the world.
However, it has high toxicity and can lead to severe and fatal immune-mediated adverse reactions, the most common of which are Enterocolitis, hepatitis, dermatitis, neuropathy and endocrinopathy
.
Therefore, Drug Y was given a black box warning by the FDA
Figure 2.
Yervoy approvals in the US
Source: Zhongkang FIC database, Zhongkang Industry Research Center
Around relatlimab, BMS has conducted 10 clinical trials involving nearly 5,000 subjects
.
These trials can show whether relatlimab acts as a boost to O or as a replacement for Y in an approved indication
Figure 3.
Safety and efficacy data of first-line melanoma treatment regimens for BMS
Source: 2021ASCO, Zhongkang Industry Research Center
The next important trial to read is relatlimab plus O, with or without chemotherapy, versus O alone in first-line treatment of NSCLC
.
The trial used PFS (progression-free survival) as the co-primary endpoint, but it is unclear whether the trial results will be used to support the marketing application
Relativity-098 (NCT05002569), which is expected to generate data by the end of 2025, is a Phase III clinical trial of O-drug + relatlimab for adjuvant melanoma treatment
.
For the monotherapy of this indication, there are not only O and Y drugs of BMS, but also Merck's K drugs, which makes the competitive landscape more complicated
.
Figure 4.
BMS clinical trials around relatlimab
Source: Zhongkang FIC database, Zhongkang Industry Research Center
The primary end date of NCT01968109 is September this year.
It is a phase I/IIa trial comparing dose escalation and cohort expansion, aiming to study the safety, safety, Tolerability and Effectiveness
.
The trial enrolled only 168 subjects when it was launched in 2013, but the enrollment target has now been expanded to 1499, the largest enrollment among the 10 trials on relatlimab, which should include more tumor types
.
While NCT01968109 is a Phase I/II trial testing overall response and adverse events, it should provide BMS insights into which cancers to focus on
.
The Phase II/III clinical trial Relativity-047 (NCT03470922) is a pivotal trial supporting the approval of Opdualag (O drug + relatlimab) for melanoma
.
The PFS in the O-drug + relatlimab group (n=355) was 10.
1 months, while the PFS in the O-drug group (n=359) was only 4.
6 months
.
In terms of safety, the incidence of grade 3-4 TRAEs (treatment-related adverse events) in the O drug + relatlimab treatment group was 19%, while the O drug + Y drug in the pivotal trial Checkmate-067 was as high as 59%
.
Although clinical trials cannot be simply and directly compared, it reflects the potential of LAG-3 monoclonal antibody relatlimab in terms of safety
.
Epilogue
Epilogue Regardless of the mechanism of action or the R&D plan of BMS, LAG-3 mAb may be a better PD-1 partner than CTLA-4
.
In the future, LAG-3 monoclonal antibody is likely to gradually replace CTLA-4 monoclonal antibody, which may require companies whose research and development pipelines include CTLA-4 inhibitors to adjust their direction and allocate resources reasonably
.
In the case of PD-1 being extremely introverted, incorporating LAG-3 into the R&D pipeline may be an option for companies
.
