FDA Approves New LAG-3 Checkpoint Inhibitor Immunotherapy Combination

Melanoma patients and oncologists finally have an exciting new checkpoint immunotherapy available to them as a treatment option, eleven years after the first checkpoint inhibitor received FDA approval and eight years since a drug targeting a new immune checkpoint pathway received a nod from the regulatory agency.

On March 18, the FDA approved relatlimab, the first immunotherapy that targets the LAG-3 immune checkpoint pathway, to be given in combination with the previously approved immunotherapy nivolumab, for people aged 12 and older with untreated unresectable or metastatic melanoma. The FDA based its approval of the combination, called Opdualag™, on data from a global, randomized phase 2-3 study, RELATIVITY-047, that demonstrated the combination doubled the median progression-free survival time for patients compared to nivolumab alone. The combination was associated with a higher incidence of immune-related side effects.

This approval introduces a new checkpoint immunotherapy target, LAG-3, to the oncologist’s arsenal. Seven of the eight FDA-approved checkpoint immunotherapies, including nivolumab, target the PD-1/PD-L1 checkpoint, and the other targets the CTLA-4 checkpoint. This class of immunotherapy operates by interfering with the immune system’s off switches. Tumors manipulate these checkpoints to hinder anti-cancer immune responses in order to protect themselves. Blocking the off switches with checkpoint inhibitors, however, enables T cells and the immune system to stay active and on the attack. Although checkpoint inhibitors have been successful in some patients when given as a single drug, approaches that combine checkpoint inhibitors with other treatments will be key to enabling immunotherapy to help more patients.

“It’s been more than a decade since first FDA approval of a checkpoint inhibitor, and since then the field has been anticipating approval of other checkpoint inhibitor therapies,” says CRI Assistant Director of Scientific Affairs Samik Upadhaya, PhD. “Now we have proof that these two checkpoint inhibitors can work together against melanoma, and this will open up research and more trials and approvals beyond just melanoma.” Upadhaya, who contributes to CRI’s regular immuno-oncology landscape analyses, also notes that, as of January 2022, there are over 2,000 active checkpoint inhibitor trials that are implementing combination immunotherapy strategies.

LAG-3 is one of a number of immune checkpoint pathways that have been studied for their therapeutic potential in cancer treatment. In 2010, longtime CRI scientist Drew M. Pardoll, MD, and Suzanne L. Topalian, MD, both of Johns Hopkins Medicine, discovered the tumor-hindering effects of the LAG-3 checkpoint inhibitor in mice. Both investigators were members of the CRI-SU2C Immunology Dream Team, and Pardoll, who was first funded by CRI in 1988, remains a member of CRI’s Scientific Advisory Council, Postdoctoral Fellowship Review Committee, and global clinical investigator network.

More recently a group of researchers from Memorial Sloan Kettering Cancer Center led by CRI physician-scientist Margaret K. Callahan, MD, PhD, found a specific pattern on immune cells that helped identify patients likely to have poorer outcomes from immunotherapy, and LAG-3 was a crucial component. Callahan and colleagues observed this pattern and its clinical relevance in patients with metastatic melanoma and, later, metastatic bladder cancer. The presence of this biological signature in melanoma and bladder cancer suggests it may be helpful in predicting treatment responses in patients with other types of cancer, too.

Currently, CRI is funding multiple grantees who are researching a variety of checkpoint pathways, how they interfere with and exhaust immune cells, and how this can be overcome in the context of cancer immunotherapy. The number of active trials exploring checkpoint inhibitors gives reason to hope that the success of the combination treatment Opdualag™ can be duplicated and implemented for other types of cancer.

Visit our immunomodulators webpage to learn more about the science behind immune checkpoint blockade treatment. Checkpoint inhibitors are just one of several types of immunomodulators, the molecules that operate on the pathways that regulate the immune system, currently approved or in clinical development for the treatment of cancer.