SEATTLE – Targeted therapies for melanoma are improving outcomes for patients with brain metastases and changing management of this dreaded complication, according to Dr. John A. Thompson, codirector of the Melanoma Clinic at the Seattle Cancer Care Alliance and a professor in the medical oncology division at the University of Washington, both in Seattle.
Dr. John A. Thompson
“We are in a new era of treatment of brain metastasis. It’s no longer just surgery and radiation therapy, but a multidisciplinary approach involving medical oncology, radiation oncology, and surgery,” he told attendees of the World Cutaneous Malignancies Congress.
Without question, surgery and radiation therapy techniques have advanced over time, and these modalities remain helpful in achieving local control of disease. Additionally, greater experience with them has improved patient selection.
For example, research has identified several predictors of benefit from stereotactic radiosurgery, such as fewer brain metastases and better performance status (J Neurosurg. 2011;114:769-79). But overall survival was fairly poor given disease elsewhere in the body. “Here’s where I think the new developments in systemic therapy may hopefully be able to start improving this curve,” Dr. Thompson said.
Toxicity of some forms of radiation therapy also remains problematic. For example, a recent randomized phase III trial in patients with up to three brain metastases showed that addition of whole-brain radiation therapy to radiosurgery improved intracranial tumor control, but at the expense of more rapid cognitive decline (ASCO 2015. Abstract LBA4). And there was no gain in overall survival.
“The changes that have happened in systemic therapy over the past 5-10 years have been very exciting,” Dr. Thompson said. By way of example, he pointed to a phase II trial that tested ipilimumab (Yervoy), an antibody to the T-cell receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA4), as induction therapy and then maintenance therapy among patients with melanoma who had brain metastases (Lancet Oncol. 2012;13:459-65).
The subset of patients who were neurologically stable and not on systemic steroids had a disease control rate of 24%, with some having objective responses, including ones in the CNS; the value was lower, at 10%, among patients who were neurologically symptomatic and on steroids, indicating more advanced disease. The 2-year overall survival rate was 26%.
“I think this is encouraging if you compare [these patients] to historical control patients with brain metastases,” said Dr. Thompson, who disclosed that he performs contracted research with Agensys, BMS, Merck, Novartis, and Pfizer.
Another phase II trial, CheckMate 204, which is currently enrolling patients, is taking the concept further, testing the combination of ipilimumab and nivolumab (Opdivo), an antibody to the cell surface receptor programmed death-1 (PD-1), as induction therapy followed by nivolumab maintenance therapy among patients with melanoma who have brain metastases. “This is I think a high-priority trial,” he asserted.
Discussing some cases from his own practice, Dr. Thompson described patient-tailored integration of the new systemic therapies with surgery and radiation therapy.
Oncologists must often deal with toxicities of these therapies as well, such as the colitis and hypophysitis related to ipilimumab therapy, and the development of resistance over time, Dr. Thompson acknowledged.
Nonetheless, the multimodality approach has led to regression and elimination of brain metastases, and even allowed some patients to achieve remission, he reported.