A combination regimen of two immunotherapies and another of two targeted therapies each significantly shrank metastatic brain tumors in at least 50 percent of patients in separate multi–center clinical trials presented at the 2017 ASCO Annual Meeting by principal investigators from The University of Texas MD Anderson Cancer Center.

Very often clinical trial protocols either exclude these patients or require them to first receive radiation treatment for their brain tumors before they can take experimental drugs, Tawbi said.

Tawbi reported the initial efficacy outcomes from the CHECKMATE–204 study. All patients were treated with ipilimumab, which blocks the CTLA–4 checkpoint on T cells, in combination with nivolumab, which inhibits activation of the PD1 checkpoint. Both checkpoints otherwise shut down T cells and thus block the anti–tumor immune response. Both drugs are infusions of targeted antibodies.

Tawbi reported the unprecedented result that 41 of 75 patients (54 percent) of the patients treated to date in the trial had their brain tumors significantly shrink. Sixteen patients had a complete response – disappearance of all tumors. Importantly, at nine months of follow up, only one of the 41 responders developed disease progression, Tawbi noted, a strong sign of durable response, a hallmark of these drugs when they are effective in patients with metastatic melanoma.

A challenge to treating tumors in the brain has been getting drugs past the blood–brain barrier, a tight seal on blood vessels that protects the brain from leakage of blood–borne toxins. It appears that this treatment may work because immune checkpoint drugs treat T cells, which can get through the barrier, rather than the hit tumor directly.

Immunotherapy poses another potential risk in patients with brain tumors, Tawbi said. When checkpoint blockade works, tumors get inflamed by the immune response, and often swell up before shrinking.

Serious treatment–related side effects, grade 3 or 4 adverse events, occurred in 52 percent of patients and were safely managed, typical of melanoma patients receiving the combination. One patient died of cardiac inflammation related to treatment.

Davies presented the results of the COMBI–MB clinical trial. All of the patients in the trial had metastatic melanoma with a BRAF V600 mutation, which is the most common oncogenic mutation in this cancer, occurring in about half of patients. Patients received dabrafenib, which targets the BRAF600 mutations, and trametinib, which binds to and inhibits MEK 1 and 2. Both BRAF and MEK are protein kinases in the RAS/RAF/MEK/ERK signaling pathway, which regulates cell growth. They are approved as oral single agents and in combination against metastatic or inoperable melanoma.

The trial included four different groups of patients, who varied in the specific types of BRAF mutations they had; whether or not they had received previous treatments for brain metastases; and whether the symptoms from the brain metastases were controlled or not. The largest group of patients in the trial had a BRAF V600E mutation, no prior treatments to their brain tumors, and symptoms caused by the brain metastases were under control.

Davies reported 44 of the 76 patients (58 percent) in that group had their brain tumors significantly shrink, and four had a complete response.

While this response rate approached those previously observed in patients without brain metastases, the duration of brain tumor control was shorter. On average, responses lasted 6–7 months, in contrast to the average duration of about one year in previous trials of patients without brain metastases, and in contrast to the results with ipilimumab and nivolumab.

Higher doses of dabrafenib and trametinib could also be explored as a strategy to improve outcomes, Davies added.

The COM