New Drug Combo Boasts Improved Outcomes, Fewer Side Effects in Melanoma

Patients with untreated, advanced melanoma lived nearly twice as long before their disease progressed when given a combination of Opdivo (nivolumab) plus relatlimab compared with those who received Opdivo alone, according to findings from the phase 2/3 RELATIVITY-047 clinical trial that were recently published in The New England Journal of Medicine.

RELATIVITY-047 Trial Results

On average, it took patients who were given the two-drug regimen 10.1 months after treatment to experience disease progression (a measure known as progression-free survival). The average progression-free survival was 4.6 months in the Opdivo-alone group of the trial. At the 12-month follow-up point, progression-free survival rates were 47.7% and 36% for patients in the Opdivo/relatlimab group and Opdivo-only group, respectively.

The drugs’ mechanism of action — or how they work — makes them pair well together. Opdivo blocks the PD-1 protein on cancer cells, allowing patients’ immune systems to recognize and attack cancer. Meanwhile, the novel drug relatlimab binds to LAG-3, a protein on T cells, amping them up to attack cancer cells.

“The results from this global effort advance the field of immunotherapy by establishing a third class of immune checkpoint inhibitors through the LAG-3 pathway and have the potential to be practice-changing,” lead author Dr. Hussein Tawbi, professor of Melanoma and Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, said in a statement.

In fact, these findings were impressive enough that the Food and Drug Administration (FDA) granted a priority review for the indication, speeding up the review process before it gets approved. The FDA is set to make a decision on whether or not to approve Opdivo plus relatlimab by March 19, 2022.

RELATIVITY-047 involved 714 patients with untreated, unresectable stage 3 or 4 melanoma. Patients were randomly selected to receive either relatlimab and Opdivo or Opdivo alone once every four weeks. The average age of participants was 63, and 8.4% (60 patients) received prior targeted or immunotherapy at least six months before being assigned to a group in the trial.

The data cutoff for researchers to process the results was March 9, 2021, with an average of 13.2 months follow-up for patients on the trial. Four-hundred seventy patients (65.8%) stopped treatment, most of them due to disease progression (36.3% and 46% in the combination and monotherapy groups, respectively).

Cancer-Fighting Efficacy With Fewer Side Effects

Patients with untreated, advanced melanoma may now be treated with a PD-1 inhibitor (like Opdivo) and/or a CTLA-4 inhibitor. While adding these two types of drugs tended to have better outcomes than giving either of them alone, the treatment comes with side effects that impact quality of life, which occurred in more than 50% of patients on the regimen.

In RELATIVITY-047, however, only 18.9% of patients in the Opdivo/relatlimab group and 9.7% of patients in the Opdivo group experienced severe (grade 3 or 4) side effects, most commonly increased levels of pancreatic and liver enzymes and fatigue. Since the drugs spark the immune system, they can lead to immune-mediated side effects. The most common ones were hypothyroidism, thyroiditis, rash and colitis. Three people and two people died in the combination and monotherapy groups, respectively. There were no new side effects in the trial that were not previously observed in research of the drugs.

“We now have evidence of a clear benefit for combination therapy compared to single-agent PD-1 inhibitors, and we’re looking forward to seeing response and overall survival data,” Tawbi said. “We’re also thinking about the populations that were excluded from this trial, including those with untreated brain metastases and uveal melanoma, so that all patients can have a chance to take advantage of the progress we’re making against melanoma.”

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