Tremendous progress in treatments for advanced melanoma has been made in the last decade. Immunotherapy—treatment that activates the immune system to find and kill cancer cells—has greatly contributed to better outcomes for people with melanoma. However, some patients will be resistant to immunotherapy drugs from the beginning of treatment (called primary resistance), and others will initially respond to treatment but then the treatment stops working (called secondary resistance). New treatments, combinations of immunotherapy drugs, and the timing of administration of these drugs are the subject of active research, with the goal of providing better outcomes for more people with melanoma.
Checkpoint molecules are expressed by immune cells and tumor cells. The tumor cells use these molecules to send a signal that puts the brakes on the immune system. This causes the immune system to ignore the cancer, and the cancer grows. Many immunotherapy drugs work by blocking checkpoint molecules, which takes the brakes off immune cells so they can find and kill the cancer cells.
Immune checkpoint inhibitor drugs were first developed against checkpoint molecules called PD-1 and CTLA-4. The first immune checkpoint inhibitor for any cancer—ipilimumab, which targets CTLA-4—was approved in 2011 for advanced melanoma. Today, several immune checkpoint inhibitor drugs are FDA approved for melanoma. These drugs work well in some patients with melanoma, but primary and secondary resistance still remains a problem. Researchers learned that other molecules also play a role in how well immunotherapy works, and they began to turn their attention to another checkpoint molecule called LAG-3.
MRA played a pivotal in supporting early research into LAG-3, including work by Drew Pardoll, MD, PhD. Early work by Dr. Pardoll and colleagues showed that PD-1 and LAG-3 work together to block immune responses against tumor cells.1 Studies like this in mice helped set the stage for clinical trials, including RELATIVITY-047, which tested inhibitors of these two molecules in people with melanoma. In 2022, based on results from the RELATIVITY-047 trial, the combination of nivolumab (which blocks PD-1) and relatlimab (which blocks LAG-3) was approved by the FDA for metastatic melanoma or melanoma that cannot be removed with surgery.
An important consideration for immune checkpoint inhibitor treatment is when to give it—before and/or after surgery to remove the tumor. The SWOG S1801 trial showed better 2-year event-free survival (EFS)—the percent of patients 2 years after beginning treatment who showed absence of disease progression or death—in stage III or IV melanoma patients who were treated with the PD-1 blocking drug, pembrolizumab, both before and after surgery (72%) compared to patients who received the drug only after surgery (49%).2,3
The phase 3 NADINA trial, led by MRA grantee Dr. Christian Blank, also showed that 1-year EFS was better in patients with stage III melanoma given ipilumumab and nivolumab before surgery (84%) than in patients given nivolumab after surgery (57%).4 You can read the plain language summary of the NADINA trial here.
These studies suggest that activating the immune system before surgery when the tumor can be recognized by the immune system is more effective than activating the immune system after surgery when all or most of the tumor is gone. The activated immune cells likely work at the site of the tumor as well as throughout the patient’s body. This may lead to elimination of tumors that would have otherwise developed in other parts of the body, producing long-term control of the cancer and preventing the cancer from coming back.3
With the understanding that the timing of giving treatment is important, researchers then conducted a phase 2 trial (NCT02519322) to test the combination of nivolumab and relatlimab given both before and after surgery in patients with surgically removable stage III or IV melanoma. Results showed that 57% of patients had a pathological complete response (meaning no evidence of live tumor). Nearly all patients who responded to this treatment remained free of disease progression or death after 2 years.5
The patient journey below highlights one participant in a clinical trial that tested the combination of nivolumab and relatlimab for advanced melanoma.
Shannon Albino, a 39-year-old elementary school teacher and mother of three, noticed a lump under her arm. After several tests, she received a diagnosis of stage III melanoma with unknown primary origin, meaning that where the melanoma started was unknown.
When discussing treatments, Shannon’s doctor suggested a clinical trial that was testing nivolumab plus relatlimab versus nivolumab alone before surgery. Shannon’s husband Rob was hesitant about clinical trials in general and concerned about the need to wait 2 months to allow time for the drug treatment before the tumor could be removed with surgery. After much discussion and learning more about how trials work, Shannon and Rob were on board with Shannon’s participation in the trial. After receiving two infusions of relatlimab and nivolumab, Shannon underwent surgery. As hospital protocols were changing due to the COVID-19 pandemic, Shannon had to recover from surgery in isolation at home due to COVID exposure in the hospital.
The surgery was successful. Continuing in the trial, Shannon then received 10 additional infusions of relatlimab and nivolumab. She had a complete response to the treatment and has no evidence of disease.
Collectively, these studies show that blocking more than one checkpoint molecule, including LAG-3, works better than blocking only one, and that the timing of when the drugs are given, before and/or after surgery, is important. Research supported by MRA continues to seek ways to refine checkpoint inhibitor treatments including treatments that block LAG-3.
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