A new type of immunotherapy can help keep an aggressive skin cancer from progressing when added to Bristol Myers Squibb’s widely used drug Opdivo, results from a large clinical trial show.

The finding, the drugmaker says, is the first definitive proof of clinical benefit for this approach to directing the immune system at tumors. The drug combination is also the first regimen for melanoma to improve on Opdivo alone, which has become a standard treatment for the skin cancer once it has spread or can’t be removed surgically.

The experimental drug tested, called relatlimab, is designed to a block a kind of protein found on immune cells that acts as a brake on their attack. Cancer cells can evade destruction by the immune system through these proteins, known as checkpoints.

Two other types of checkpoint blockers are cleared for use in a wide range of tumors: PD-1 inhibitors like Opdivo and Merck & Co.’s Keytruda and CTLA-4 inhibitors like Bristol Myers’ earlier drug Yervoy. Relatlimab is aimed at another checkpoint protein dubbed LAG-3.

“This is the first Phase 3 study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy for patients with cancer,” said Evan Lipson, an oncologist at the Johns Hopkins Kimmel Cancer Center and lead author of the study, in a prerecorded presentation of the data. “[I]t establishes the LAG-3 pathway as the third immune checkpoint pathway in history after CTLA-4 and PD-1 for which blockade appears to have clinical benefit.”

Data from the Phase 3 study were disclosed in a study abstract released ahead of next month’s meeting of the American Society of Clinical Oncology. While Bristol Myers Squibb said in March the study succeeded, this is the first time detailed results are being disclosed.

The study, which enrolled just over 700 people with advanced melanoma, tested relatlimab together with Opdivo against Opdivo by itself. Participants had not previously been treated for their disease.

After a median follow-up of just over a year, results showed the combination reduced the risk of disease progression by 25% compared to Opdivo monotherapy, a statistically significant difference. Median progression-free survival — a measure of the length of time until disease progression or death — was 10.1 months among trial volunteers given both drugs and 4.6 months among those given only Opdivo.

“[The study] demonstrates the benefit in progression-free survival of the combination over [Opdivo] monotherapy,” said Jonathan Cheng, Bristol Myers’ head of oncology development, in an interview. “It’s not a low bar.”

Bristol Myers previously tested combinations of Opdivo and Yervoy in advanced melanoma alongside Opdivo, but pitted the two-drug regimen against Yervoy alone, rather than Opdivo. The company will present 6.5-year follow-up from that study at ASCO

One big hurdle to use of Opdivo and Yervoy — a combination approved for multiple tumor types — is the drugs’ significant toxicity, including potentially dangerous autoimmune side effects, when paired with one another. On that score, relatlimab and Opdivo may prove comparatively more tolerable.

Lipson, the study author, noted that while the incidence of severe side effects was higher with the two drugs than with Opdivo alone, “these adverse events occurred at a lower rate than has been observed with other immunotherapy combinations.”

Nineteen percent of patients given relatlimab and Opdivo experienced Grade 3 or Grade 4 side effects related to treatment, versus about 10% of those who received Opdivo. There were three deaths in the trial that researchers judged connected to combination treatment, including one from an immune reaction known as HLH. Two deaths of study participants given Opdivo were determined to be treatment-related.

Data from the study will be presented at ASCO on June 6. The study continues to assess the rate of treatment response and overall survival, which are secondary goals after progression-free survival. It’s unusual for cancer drug studies to read out progression-free survival results first, before the response rates are known, but Bristol Myers’ Cheng said that’s how the study was designed from the outset, based on what the company saw in earlier study data.

Progression-free survival is considered a “surrogate” measure for survival, although there is debate among experts over how predictive the benefit really is.

Other companies are interested in LAG-3 as well. At ASCO, both Merck and partners Sanofi and Regeneron will present data from early studies of their LAG-3 inhibitors in colon cancer and melanoma, respectively. Boehringer Ingelheim, Novartis and several other companies are testing versions of their own as well.

The accelerating research into LAG-3 is the latest example of drugmakers’ efforts to replicate the success they found with PD-1 and CTLA-4. Despite the remarkable responses some patients experience with immunotherapy in certain cancers like lung, skin and kidney, many don’t experience a benefit. Developers have spent years of research exploring why as well as testing other drugs that may work in tandem or in similar ways.

Most efforts have come up short, although there are other targets than LAG-3 that have shown promise recently.

Bristol Myers, buoyed by the positive results to date with relatlimab, has launched a large clinical program testing the drug in various combinations. According to Cheng, non-small cell lung cancer and hepatocellular carcinoma are two cancers the company is particularly focused on.

The company plans to discuss the melanoma data with regulators, although Cheng would not comment further.