Ipilimumab/Nivolumab Improves Survival in Melanoma With Brain Metastases

The CheckMate 204 study showed overall survival benefit of combination nivolumab/ipilimumab to patients with melanoma brain metastases.

An immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated overall survival (OS) benefit in patients with melanoma and brain metastases, according to a press release from The University of Texas MD Anderson Cancer Center.1 The final results of the immune checkpoint inhibitor combination’s effectiveness, especially against asymptomatic metastases, were published in The Lancet Oncology.2

The randomized phase 2 CheckMate 204 study (NCT02320058) investigators first reported the efficacy of the therapy in patients with melanoma brain metastases (MBM) who were asymptomatic in the New England Journal of Medicine in 2018.3 The 3-year follow-up data were published in The Lancet Oncology with final results and additional data on patients who were symptomatic and/or required treatment with corticosteroids.2

A population of 119 patients with MBM of 0.5 cm to 3.0 cm in diameter were treated with nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks for 4 doses, followed by maintenance nivolumab monotherapy for up to 24 months.

“Historically, many patients with brain metastases have been excluded from clinical trials,” lead author Hussein Tawbi, MD, PhD, professor of Melanoma Medical Oncology and codirector of the Brain Metastasis Clinic at MD Anderson, said in a statement.1 “Now, we’re showing that it’s possible to run trials specifically dedicated to this population.”

At the 3-year follow up, the study population had an OS rate of 71.9% (95% CI, 61.8%-79.8%).2 Among those whose disease responded to treatment within 12 weeks, OS was 92%.1 However, in the 18 patients with neurological symptoms or who required corticosteroid therapy, there was an OS rate of 36.6% (95% CI, 14.0%-59.8%).2 The OS improved for some patients who did now show a response to the combination immunotherapy, suggesting that its effects are not fully assessed by imaging techniques, or that subsequent therapy was effective.

Prior to the use of nivolumab/ipilimumab combination, the 1-year survival rate for patients with MBM was 20%.1 “Inducing an intracranial response with combination immunotherapy has a direct and lasting impact on survival for patients whose melanoma has spread to the brain,” said Tawbi. “We’ve shown that this treatment offers a chance of long-term survival to patients with a historically dire prognosis.”

The primary end point was intracranial clinical benefit rate (CBR) for a timeframe of up to 66 months, as defined by the number of patients who achieved a complete response, partial response, or stable disease for at least 6 months. The intracranial CBR was 57.4% (95% CI 47.2%-67.2%) in patients with MBM who were asymptomatic, while the overall response rate was 53.5% (95% CI, 43.3%-63.5%). The investigator-assessed CBR in patients with symptomatic MBM or receiving corticosteroids was 16.7% (95% CI, 3.6%-41.4%).2 Blinded independent central review had a high concordance with the investigators’ assessments.

Among the patients with asymptomatic MBM, 55.4% had grade 3 or grade 4 treatment-related adverse events (TRAEs), leading 28.7% of patients to discontinue treatment. Among those with symptomatic MBM or those receiving steroids, 66.7% had grade 3 TRAEs and 16.6% discontinued treatment, but none experienced grade 4 TRAEs.

“Combination immunotherapy remains a highly toxic treatment regimen, so one of our next areas of focus is developing treatments that are safer for patients and still just as effective,” Tawbi said.

No new TRAEs were reported at the 3-year follow-up. No new safety concerns were found in the follow-up, and the overall safety profile was to that reported in patients with melanoma without MBM. Known serious TRAEs include colitis, diarrhea, pituitary inflammation, and elevated liver enzymes. One patient death occurred because of treatment-related myocarditis.

“These results confirm that combination immunotherapy is effective and should be considered as a front-line option for asymptomatic patients with melanoma brain metastases,” Tawbi said. “The study also highlights the ongoing need for effective options for symptomatic patients, and the opportunity to help this population further by working on ways to eliminate the need for steroids."


1. Combination immunotherapy improves survival for patients with asymptomatic melanoma brain metastases. The University of Texas MD Anderson Cancer Center. Published November 10, 2021. Accessed November 12, 2021. https://bit.ly/3HbAyl3

2. Tawbi HA, Forsyth PA, Hodi FS, et al. Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study. Lancet Oncol. Published November 10, 2021. Accessed November 16, 2021. doi:10.1016/S1470-2045(21)00545-3

3. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453