Immunotherapy Combination's Effectiveness Against Brain Metastases Draws Attention

Many cancers, in their advanced stages, develop brain metastases . Metastasis means cancer cells spreading beyond their organ of origin to other tissues, at which point cancer is called stage 4. Among metastases, brain metastases attract intense interest from doctors, patients and relatives. The cancers most commonly spreading to the brain are lung, breast and colon cancer, malignant melanoma (skin cancer), and lymphoma. When cancer spreads to the brain, it is called cancer metastatic to the brain rather than brain cancer; for example, lung cancer with brain metastases...

Much oncology research aims to prevent or treat metastases. However, brain metastases are harder to treat than other metastases, primarily because the blood–brain barrierreduces drug entry into the brain. The barrier is formed by nervous system glial cells and allows substances such as glucose (sugar) and caffeine through but excludes larger molecules such as some drugs.

Because brain metastases are known to be difficult to treat, in clinical trials testing new cancer drugs, patients with brain metastases are not enrolled early. Drugs are generally tested in this patient group after approval, so a new drug being effective against brain metastases is particularly noteworthy.

On 23 August 2018, NEJM published a study finding that, in patients with brain metastases from the skin cancer malignant melanoma,a dual immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was as effective in treating brain metastases as extracranial metastases.

Study Details

Brain metastases are a leading cause of death in stage 4 melanoma patients. Previous trials of nivolumab combined with ipilimumab for metastatic melanoma had excluded patients with brain metastases. This study evaluated the effectiveness and safety of nivolumab plus ipilimumab in melanoma patients who had not previously received treatment for brain metastases.

This open-label, multicenter, CheckMate 204 phase 2 clinical trial enrolled patients with at least one measurable brain metastasis 0.5 to 3 cm in diameter, without prior radiotherapy or neurological symptoms (brain-related complaints), totaling 94 patients.

Patients received nivolumab (1 mg per kilogram) plus ipilimumab (3 mg per kilogram) every 3 weeks for 4 doses. Nivolumab (3 mg per kilogram) then continued every 2 weeks until progression (disease worsening) or unacceptable adverse effects.

The primary endpoint was defined as the percentage of patients with stable disease for at least 6 months, a complete response or a partial response, called the intracranial clinical benefit rate as the selected endpoint.

Study Results

• After a median follow-up of 14 months in 94 patients, the intracranial clinical benefit rate was % 57.
• With this combination immunotherapy, the complete response rate was % 26, the partial response rate % 30, and stable disease for at least 6 months % 2.
• The extracranial (outside the brain) clinical benefit rate was % 56.
• Treatment-related grade 3 or 4 (severe) adverse effects were reported in % 7 of patients (% 55 of these adverse effects were brain- and nervous-system-related). One patient died from immune -related myocarditis (inflammation of the heart muscle). The adverse effect/safety profile of this dual immunotherapy resembled that reported in melanoma patients without brain metastases.

In conclusion, the study found nivolumab combined with ipilimumab immunotherapy to have clinically meaningful effectiveness in melanoma patients with brain metastases, comparable to that against extracranial metastases.