Rapid hyperacute intracranial deterioration following initiation of ipilimumab/nivolumab in BRAF V600E-mutant melanoma of unknown primary with brain metastases after BRAF/MEK inhibitor therapy: a case series.

Therapeutic sequencing in BRAF-mutant melanoma with active brain metastases remains clinically challenging. Limited data exist regarding outcomes following transition from BRAF/MEK inhibition to combined immune checkpoint inhibition in patients with melanoma of unknown primary (MUP). We retrospectively reviewed three patients with BRAF V600E-mutant MUP treated at a single tertiary oncology center. All patients had previously received BRAF/MEK inhibitor therapy for 7-12 months before developing brain metastases. Ipilimumab/nivolumab was initiated following disease progression after a washout interval exceeding 7 days. Clinical course, imaging findings, and laboratory parameters were analyzed. Patients were aged 41-64 years and had preserved performance status (Eastern Cooperative Oncology Group: 0) prior to intracranial progression. Brain metastases (2-3 lesions per patient) were confirmed on MRI without evidence of hemorrhage prior to immunotherapy initiation. All patients had elevated lactate dehydrogenase at the time of transition. Neurological symptoms developed rapidly within 2-5 days after initiation of immunotherapy. All required high-dose corticosteroids (dexamethasone: 16 mg intravenously daily). No overt immune-related laboratory toxicities were observed. All three patients died within 2 weeks of starting combined immune checkpoint inhibition. Patients with BRAF V600E-mutant MUP and active brain metastases with elevated lactate dehydrogenase may represent a particularly high-risk subgroup in whom immediate transition from targeted therapy to dual immune checkpoint inhibition can be followed by hyperacute intracranial clinical deterioration. These observations underscore the importance of therapeutic sequencing.