First-Line Nivolumab/Ipilimumab Garners Durable Responses in Asymptomatic Melanoma Brain Metastases


Patients with melanoma who have asymptomatic brain metastases had long-lasting responses after being treated with first-line nivolumab and ipilimumab.

Treatment with first-line nivolumab (Opdivo) and ipilimumab (Yervoy) resulted in a durable survival benefit for patients with melanoma brain metastases, according to results from the phase 2 CheckMate 204 trial (NCT02320058).1

Cohort A (n = 101), a population of asymptomatic patients, experienced a clinical benefit (CBR) rate of 57.4% (95% CI, 47.2%-67.2%) compared with 16.7% (95% CI, 3.6%-41.4%) in cohort B (n = 18), who were symptomatic. Additionally, the investigator-assessed overall response rate (ORR) was 53.5% (95% CI, 43.3%-63.5%) for cohort A and 16.7% (95% CI, 3.6%-41.4%) for cohort B. Additionally, patients in cohort A had a 36-month intracranial progression-free survival (PFS) rate of 54.1% (95% CI, 42.7%-64.1%) as well as an overall survival (OS) rate of 71.9% (95% CI, 61.8%-79.8%). The 36-month PFS and OS rates for cohort B were 18.9% (95% CI, 4.6%-40.5%) and 36.6% (95% CI, 14.0%-59.8%), respectively.

“Inducing an intracranial response with combination immunotherapy has a direct and lasting impact on survival for patients whose melanoma has spread to the brain,” lead author Hussein Tawbi, MD, PhD, professor of melanoma medical oncology and co-director of the brain metastasis clinic at MD Anderson Cancer Center, said in a press release.2 “We’ve shown that this treatment offers a chance of long-term survival to patients with a historically dire prognosis.”

The open-label, multicenter trial was conducted at 28 sites in the United States and enrolled patients who were 18 years of age with histologically confirmed metastatic melanoma and at least 1 non-irradiated brain metastasis of 0.5 cm to 3.0 cm in diameter. Prior stereotactic radiotherapy or excision of up to 3 brain metastases were allowed provided the treatment was completed at least 3 weeks prior to the start of treatment and 1 lesion was not irradiated.

All patients received a 1 mg/kg dose of nivolumab with 3 mg/kg of ipilimumab intravenously once evert 3 weeks for 12 weeks from the induction phase. This was followed by 3 mg/kg of nivolumab intravenously every 2 weeks for 24 months or until disease progression or unacceptable toxicity.

The primary end point of the trial was intracranial CBR, with key secondary end points including extracranial and global CBR; intracranial, extracranial, and global ORR and PFS; and OS.

A total of 165 patients were enrolled from February 19, 2015, to November 1, 2017. Cohort A had a median follow up of 34.3 months (IQR, 14.7-36.4) and cohort B had a median follow up of 7.5 months. In total, 58% of patients in cohort A and 28% of patients in cohort B remained in follow up at the database cut off. The median duration of therapy was 3.4 months for cohort A, with 57% of the population going on to the maintenance phase of the study. Those in cohort B had a median treatment duration of 0.7 months and 22% went on to the maintenance phase; 78% of this population received 1 to 2 doses. Nineteen percent of patients in cohort A and 22% in cohort B went on to receive subsequent systemic therapy.

Additional findings from the study indicated that those in cohort A had an intracranial complete response rate of 33% vs 17% in cohort B. Patients in cohort A experienced a tumor volume reduction of 69.0% and 84% of patients had an ongoing intracranial response. The median duration of response had not been reached and 58% of responses lasted for over 2 years.

Grade 3/4 treatment-related adverse effects (TRAEs) were found to occur in 55% of patients in cohort A and 67% of patients in cohort B. The most common grade 3/4 TRAE was increased alanine (ALT) or aspartate aminotransferase (15% each) in cohort A, with no grade 3 TRAEs occurring in more than 1 patient in cohort B. No grade 4 events were reported in cohort B. Grade 3/4 neurological TRAEs occurred in 7% and 17% of patients in cohorts A and B, respectively. Common immune-mediated AEs in both cohorts included hepatitis rash, and hypothyroidism. Additionally, serious TRAEs included colitis, diarrhea, hypophysis, and increased ALT.

“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. “Historically, many patients with brain metastases have been excluded from clinical trials. Now, we’re showing that it’s possible to run trials specifically dedicated to this population.”


  1. 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 online November 10, 2021. doi: 10.1016/S1470-2045(21)00545-3
  2. Combination immunotherapy improves survival for patients with asymptomatic melanoma brain metastases. News release. MD Anderson. November 10, 2021. Accessed November 12, 2021.
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