Treatment with ipilimumab plus nivolumab improves long-term survival in melanoma patients with asymptomatic brain metastases, according to the results of the NIBIT-M2 trial presented at AACR 2026.
“The 10-year results of the NIBIT-M2 study, with the longest follow-up available to date in melanoma patients with asymptomatic brain metastases, continue to show persistent long-term therapeutic efficacy of ipilimumab plus nivolumab,” said lead study author Dr Anna Maria di Giacomo, University of Siena, Center for Immuno-Oncology, University Hospital of Siena, NIBIT Foundation Onlus, Siena, Italy.
In the NIBIT-M2 trial, Di Giacomo and her team recruited 80 melanoma patients with active, untreated, asymptomatic brain metastases from nine Italian centres between January 2013 and September 2018. Of these, 76 were randomly allocated to receive fotemustine (arm A; n=23), ipilimumab plus fotemustine (arm B; n=26), or ipilimumab plus nivolumab (arm C; n=27).
Overall survival (OS) was the primary endpoint, while intracranial progression-free survival (iPFS) was secondary. Exploratory analyses were performed on cell free (cf) DNA plasma samples collected at baseline and week 12 on therapy.
Furthermore, Di Giacomo and colleagues used IchorCNA to estimate tumour fraction from low pass whole-genome sequencing. They also calculated the tumour-specific methylation Score (T-meth Score) as the ratio between the coverage over methylated regions analysed by cf-methylated DNA immunoprecipitation and high-throughput sequencing and melanoma-specific methylated regions previously identified in The Cancer Genome Atlas melanoma cohort.
Over a median follow-up of 125 months, patients attained a median OS of 8.5 months (95 percent confidence interval [CI], 4.8‒12.2) in arm A, 8.2 months (95 percent CI, 2.1‒14.3) in arm B, and 29.2 months (95 percent CI, 0‒73.5) in arm C. [AACR 2026, abstract CT008]
At 10 years, the OS rates were 13.0 percent (95 percent CI, 0‒26.7), 7.7 percent (95 percent CI, 0‒17.9), and 31.2 percent (95 percent CI, 13.0‒49.4) in arms A, B, and C, respectively. The corresponding 10-year melanoma-specific survival was 13.0 percent (95 percent CI, 0‒26.7), 7.7 percent (95 percent CI, 0‒17.9), and 35.1 percent (95 percent CI, 16.3‒53.9).
Moreover, the iPFS rate at 10 years was 4.3 percent (95 percent CI, 0‒12.7) in arm A, 7.7 percent (95 percent CI, 0‒17.9) in arm B, and 20 percent (95 percent CI, 3.9‒35.7) in arm C.
Tumour fraction
At baseline, Di Giacomo and her team stratified patients according to the median values of tumour fraction (n=57; median 0.022) and of T-meth Score (n=53; median 0.096). They observed a significantly higher median OS among patients with tumour fraction (22.3 vs 8.2 months; p=0.033) and T-meth Score (26.3 vs 7.9 months; p=0.002) below the median values.
Notably, patients with low tumour fraction and T-meth Score were “enriched” at baseline in those treated with ipilimumab plus nivolumab. Patients with an OS above the median (26.3 months for tumour fraction and 24.0 months for T-meth Score) were found to have a reduction in tumour fraction (n=29) and T-meth Score (n=24) at week 12.
“Plasma-derived TF and T-meth Score may predict long-term survival of melanoma patients with asymptomatic brain metastases treated with ipilimumab plus nivolumab,” Di Giacomo said.