Pembrolizumab Induces Responses in Melanoma Patients With Brain Mets

Early results from an ongoing trial suggest that pembrolizumab has promising activity in untreated melanoma patients with brain metastases. The data were presented at the Society for Melanoma Research 2015 International Congress, held November 18–21 in San Francisco.

About half of metastatic melanoma patients develop brain metastases. “Historically, the brain was considered an ominous site, and survival in older studies is about 2 to 4 months. Whole brain radiation therapy does not clearly impact survival, and controls brain lesions for weeks only,” said Harriet Kluger, MD, professor of medicine (medical oncology) at Yale Cancer Center.

Stereotactic radiosurgery has become the standard approach at many places, although it is still controversial and costly, Dr. Kluger said. “New technology enables efficient and accurate treatment of up to about 30 metastases in a single setting, although most institutions do up to 4 at a time,” she said. With recent advances in local therapy, including stereotactic radiosurgery and new surgical techniques, median survival has doubled in this population.

Studies of newer drugs in patients with brain metastasis have lagged behind other studies. “New, comprehensive approaches involving systemic therapy are needed for these patients,” she said. “There is now a large menu of clinical trials of both targeted therapy and immunotherapy for this population. We have a diversity of endpoints, radiographic criteria, and designs.”

Yale researchers have found NRAS-mutant melanomas have numerous and recurrent brain metastases. “No other obvious features, such as age, gender, or histologic type, are associated with size, number, and survival,” she said.

At Yale, researchers have begun a phase II trial of pembrolizumab for untreated brain metastasis in melanoma and lung cancer. Patients included in the trial have at least one untreated brain metastasis of 5 to 20 mm and no neurologic symptoms or steroid requirement.

Dr. Kluger reported the results of the first 18 of 22 melanoma patients (median age 65). About one-third have BRAF mutations and elevated LDH levels. Some 22% had prior therapy with BRAF inhibitors.

Treatment-related adverse events were as expected for patients treated with pembrolizumab, and included dermatologic and constitutional symptoms, and arthralgias. Neurologic adverse events included seizures in three patients and focal symptoms related to central nervous system (CNS) edema in five patients.

The drug showed activity in the brain. Fourteen patients were evaluable, four patients achieved partial response (PR) and disease stabilized in three patients; seven patients had progressive disease, including four patients with prior BRAF inhibitor therapy who progressed rapidly.

Extra-cerebral responses included one complete response and three PRs and were concordant with brain response, she said.

All responders have remained in response for up to 17 months. Progression-free survival among the four responders ranges from 6 to 17 months. Overall survival has not yet been reached.

In conclusion, Dr. Kluger said: “Responses in the body and brain are largely concordant in our pembrolizumab trial. Overall survival appears to exceed the expected in this patient population.”

CNS symptoms controllable with anticonvulsants and transient use of steroids might contribute to early withdrawal, she said, adding that stereotactic radiosurgery is sometimes needed to control hemorrhage or discordant growth in the setting of overall response.