Ipilimumab plus nivolumab improved survival when compared with ipilimumab plus fotemustine or fotemustine alone in patients with melanoma and asymptomatic brain metastases, according to phase 3 study results published in Clinical Cancer Research.

Previous results from phase 2 trials showed “encouraging activity with ipilimumab plus nivolumab and ipilimumab plus fotemustine” in patients with melanoma and brain metastases, meriting further investigation in this “hard-to-treat” patient population, the study authors wrote.

The phase 3 NIBIT-M2 trial (ClinicalTrials.gov Identifier: NCT02460068) enrolled 80 patients with metastatic melanoma and active, asymptomatic, and untreated brain metastases.  

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The patients were randomly assigned to receive fotemustine alone (n=27), ipilimumab plus fotemustine (n=26), or ipilimumab plus nivolumab (n=27). Of the 80 patients randomized, 76 received treatment. Baseline characteristics were similar across the treatment arms.

The median follow-up was 52 months. The median overall survival (OS) was 29.2 months with ipilimumab-nivolumab, 8.2 months with ipilimumab-fotemustine, and 8.5 months with fotemustine monotherapy.

The 4-year OS rate was 41% with ipilimumab-nivolumab, 10% with ipilimumab-fotemustine, and 11% with fotemustine alone.  The 4-years OS rate was significantly higher with ipilimumab-nivolumab than with fotemustine alone (P =.015).

The risk of death was not significantly different between the ipilimumab-fotemustine and fotemustine-only arms (hazard ratio [HR], 1.09; 95% CI, 0.59-1.99; P =.78).

However, ipilimumab-nivolumab resulted in a 56% reduction in the risk of death when compared with fotemustine alone (HR, 0.44; 95% CI, 0.22-0.87; P =.017), although this did not reach the prespecified level of significance.

The median intracranial progression-free survival (PFS) was 8.7 months with ipilimumab-nivolumab, 3.3 months with ipilimumab-fotemustine, and 3.0 months with fotemustine monotherapy. These values were identical to the median global PFS values in each of the treatment arms.

Grade 3-4 treatment-related adverse events (AEs) occurred at a lower frequency in patients treated with ipilimumab-nivolumab (30%) than in patients treated with ipilimumab-fotemustine (69%) or fotemustine alone (48%).  

Myelotoxicity was common in the fotemustine monotherapy arm and the ipilimumab-fotemustine arm. Immune-related AEs were common in the ipilimumab-fotemustine and ipilimumab-nivolumab arms.

There were no treatment-related deaths or unexpected toxicities reported during the study.

“The overall and long-term survival results of our phase 3 NIBIT-M2 study in patients with melanoma with asymptomatic brain metastases strongly contribute [to] breaking the dogma that immunotherapy has limited efficacy in brain metastases,” the study authors wrote.

“Recognition of the value of immunotherapy in treating asymptomatic melanoma brain metastases suggests that, in first-line patients, the role of surgery and RT [radiotherapy] might be reappraised for this subgroup of patients and paves the way to broadening investigation of immunotherapy in tumors of different histology when metastatic to the brain,” they added.

Disclosures: This research was supported, in part, by Bristol Myers Squibb. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Di Giacomo AM, Chiarion-Sileni V, Del Vecchio M, et al. Primary analysis and 4-year follow-up of the phase III NIBIT-M2 trial in melanoma patients with brain metastases. Clin Cancer Res. Published online June 10, 2021. doi:10.1158/1078-0432.CCR-21-1046