Unmasking of intracranial metastatic melanoma during ipilimumab/nivolumab therapy: case report and literature review

Background: While data from several studies over the last decade has demonstrated that introduction of immunologic checkpoint blockage therapy with anti-CTLA-4/PD-1 drugs leads to improved survival in metastatic melanoma patients, relatively little is known about brain-specific therapeutic response and adverse events in the context of immunotherapeutic treatment of intracranial disease. Here we report two independent cases of new intracranial metastases presenting after initiation of combined checkpoint blockade Ipilimumab and Nivolumab for recurrent metastatic melanoma in the context of positive systemic disease response. Case presentation: Case #1: A 43-year-old Caucasian male with Stage III melanoma of the left knee had subsequent nodal, hepatic and osseous metastases and was started on ipilimumab/nivolumab. He developed an intractable headache one week later. MRI revealed new enhancing and hemorrhagic brain metastases. After 6 weeks of immunotherapy, there was interval hemorrhage of a dominant intracranial lesion but substantial improvement in systemic metastatic disease. Durable, near complete intracranial and systemic response was achieved after completion of both induction and maintenance immunotherapy. Case #2: A 58-year old Caucasian woman with stage II melanoma of the right index finger developed cutaneous, pulmonary and hepatic metastases within 4 months of adjuvant radiation. Although combined checkpoint blockade resulted in improvement in both cutaneous and systemic disease, brain MR performed for eye discomfort demonstrated new enhancing and hemorrhagic brain metastases. Serial MR imaging five months later revealed only a solitary focus of brain enhancement with continued improved systemic disease. Conclusions: These cases raise the question of whether the initial immune activation and modulation of the blood brain barrier by Ipilimumab/Nivolumab somehow "unmasks" previously clinically silent metastatic disease, rather than representing new or progressive metastatic disease. An overview of currently available literature discussing the role of immune checkpoint blockade in the treatment of intracranial metastatic melanoma will be provided, as well as discussion highlighting the need for future work elucidating the response of brain metastases to anti-CTLA/PD-1 drugs and documentation of brain-specific adverse events.