Immunotherapy Combo Produces Durable Responses in Melanoma Brain Metastases

More than half of patients with asymptomatic melanoma brain metastases obtained durable responses to the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy), according to long-term follow-up from a prospective study.

The 3-year intracranial progression-free survival (PFS) was 54.1%, and overall survival (OS) was 71.9%. A third of patients with asymptomatic brain metastases had complete intracranial responses by investigator assessment. Patients with symptomatic brain metastases derived considerably less benefit from the treatment, as reflected in a 16.7% response rate and 3-year OS of 36.6%.

The most common treatment-related adverse events (TRAEs) were increased liver enzymes, Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and coauthors, reported in The Lancet Oncology.

“The most important aspect here is that the combination immunotherapy is capable of having a great response in the brain, leading to improved survival in patients,” Tawbi told MedPage Today. “This is all new. We knew that immunotherapy is capable of good responses and improved survival in patients without brain metastases, but for the first time we have evidence of that happening in patients with brain metastases.”

“We believe that this should change practice, as it has to a degree, but now that we have survival data, I think it’s very clear that this is the way to go for this population of patients,” he added.

The brain is one of the most common sites of metastasis for melanoma, affecting up to 40% of patients in some studies and series. Historically, survival after diagnosis of brain metastases has ranged from 3 to 13 months. Immune checkpoint inhibitors have proven activity in advanced melanoma, but few clinical trials included patients with untreated asymptomatic brain metastases or those with symptomatic brain lesions, said Tawbi.

Trials that have included patients with melanoma brain metastases often involved single-agent immunotherapy or targeted therapies, he continued. A recent systematic review and meta-analysis showed that combination immunotherapy improves PFS and OS as compared with single-agent immunotherapy or combination targeted agents.

Tawbi and coauthors’ findings came from continued follow-up of the CheckMate 204 trial, which demonstrated intracranial activity in patients with melanoma and asymptomatic brain metastases. As previously reported, the study showed that intracranial activity was equivalent to extracranial activity with nivolumab and ipilimumab.

The updated report included intracranial PFS and OS after a median follow-up of 34.3 months. The trial included 101 patients with asymptomatic melanoma brain metastases and 18 with symptomatic brain metastases (median follow-up of 7.5 months).

The results showed an investigator-assessed intracranial benefit (response plus stable disease) rate of 57.4% in the patients with asymptomatic brain metastases versus 16.7% in those with symptomatic brain lesions. Objective responses occurred in 54 (53.5%) and three (16.7%) patients with asymptomatic and symptomatic brain metastases, respectively. In general, intracranial activity correlated with the combination’s extracranial antitumor activity.

Grade 3/4 elevations in alanine aminotransferase and aspartate aminotransferase occurred in 15 patients each in the patients with asymptomatic brain lesions. No grade 3 TRAEs occurred in more than one patient with symptomatic brain metastases, and no patient in that subgroup developed a grade 4 TRAE.

Though encouraging, the results also pointed to several areas of unfinished work, Tawbi noted.

“There are still 45% of patients who don’t respond, and we need to work on that,” he said. “Secondly, patients with symptomatic brain lesions, who require steroids, don’t do as well and their response rate is about 20%. We have to figure out how to improve outcomes in that population.”

He continued: “The last thing we have to work on is improving the tolerability. The combination is effective, but about 35% of patients had some type of toxicity. We hope to come up with newer approaches that give us the same benefits with less toxicity. One such approach is the new combination of nivolumab and relatlimab. That combination has yet to be studied in the brain, but we’re going to be running a trial to study that to see whether we can improve on the outcomes without increasing toxicity.”