Immunotherapy for CNS Melanoma: RELATIVITY-020’s Intracranial Efficacy Data
Panelists discuss evolving treatment strategies for metastatic melanoma with asymptomatic brain metastases, highlighting the superiority of PD-1 plus CTLA-4 combination therapy for durable intracranial responses, while noting that newer immunotherapy combinations like PD-1 plus LAG-3 show promise but require further evidence before altering current standards of care.
In cases of metastatic melanoma with asymptomatic brain metastases, treatment strategies have evolved significantly. Historically, patients with brain metastases were immediately referred to radiation oncology or neurosurgery, often before any systemic therapy was considered. However, with advances in targeted therapies and immunotherapies, systemic options have shown meaningful intracranial activity. Targeted therapies can induce high response rates in the brain, but their durability is typically lower compared to extracranial sites. Similarly, single-agent PD-1 therapy produces durable responses, but the response rates are lower in the brain than elsewhere.
The combination of CTLA-4 and PD-1 inhibitors has demonstrated the most promising results for durable intracranial responses. In previous studies, this combination achieved high response rates and long-lasting outcomes in patients with asymptomatic brain metastases who were not on steroids. It has become the standard of care in this setting. Although newer combinations like PD-1 and LAG-3 inhibitors are being explored, their intracranial efficacy remains less defined. Retrospective and exploratory analyses from clinical trials suggest some degree of brain activity, with one recent review showing a 22% intracranial response rate in patients who had previously progressed on PD-1 therapy—similar to their extracranial response rates.
While the data on the newer immunotherapy combinations are encouraging, they are not yet practice-changing. Until prospective, dedicated trials confirm their effectiveness in the brain, dual checkpoint blockade with PD-1 and CTLA-4 remains the preferred first-line approach for patients with untreated brain metastases. Future directions aim to clarify whether less toxic combinations can achieve similar outcomes, potentially allowing treatment decisions to consider other clinical factors such as tumor burden, LDH levels, and patient symptoms, rather than relying solely on the presence of brain metastases.
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