The combination of nivolumab with ipilimumab is an effective treatment option for patients with advanced melanoma with asymptomatic brain metastases and should be considered for first line-therapy, according to study results published in Neuro-Oncology.

Treatment options for patients with melanoma with brain metastases are limited, and frequently patients with active brain metastases are excluded from clinical trials. Previously, in patients with melanoma and asymptomatic brain metastases, the combination of nivolumab plus ipilimumab provided an intracranial response rate of 55%.

In this study, researchers reported the outcomes of combination immunotherapy in symptomatic and/or patients treated with corticosteroids at the time of introducing treatment, as well as extended follow-up data for the entire asymptomatic cohort.


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This open-label, nonrandomized, phase II trial included adults with histologically confirmed melanoma and evidence for brain metastases measuring between 0.5 and 3.0 cm on magnetic resonance imaging of the brain. Study researchers classified participants as asymptomatic (Cohort A) or as having stable neurologic symptoms and/or receiving corticosteroids (Cohort B).

All patients received combination of nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, every 3 weeks for 4 doses, after which they received nivolumab monotherapy at 3 mg/kg every 2 weeks. Treatment was at least 6 months and continued until disease progression, unacceptable toxicity, or 24 months.

The primary endpoint was intracranial clinical benefit rate, including complete response, partial response, or stable disease for at least 6 months.

The study sample included 18 patients with symptomatic brain metastases and/or treated with corticosteroid in Cohort B and 101 corticosteroid-free patients with asymptomatic brain metastases in Cohort A.

The median follow-up for patients in Cohort B was 5.2 months, and patients received a median of 1 combination dose. Intracranial response was reported for 4 of 18 patients, with an objective response rate of 22.2% for intracranial, extracranial, and global disease. Responses were observed in 2 of 12 corticosteroid-treated patients and in 2 of 6 patients with symptomatic brain metastases.

Median progression free survival in symptomatic patients was 1.2 months (95% CI, 0.7-1.3) for intracranial disease, and median overall survival was 8.7 months (95% CI, 1.8-not reached).

Data on longer follow-up of 101 patients with asymptomatic brain metastases (median follow-up, 20.6 months) confirmed the durable efficacy of the combination treatment with a clinical benefit rate of 58.4% (59 of 101 patients). Median duration of response, progression free survival, and overall survival were not reached.

The study had several limitations, including the lack of an independent review of the imaging data, small sample size, and the exclusion of patients with unstable neurologic symptoms, recent seizures, or a higher corticosteroid dose requirement.

“Based on our long-term follow-up data of Cohort A, we believe the standard treatment for patients with advanced melanoma with asymptomatic brain metastases who are candidates for immunotherapy should be 1 mg/kg nivolumab plus 3 mg/kg ipilimumab,” concluded the study researchers.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Tawbi HA, Forsyth PA, Hodi FS, et al. Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204). Neuro Oncol. Published online April 21, 2021. doi:10.1093/neuonc/noab094