Immunotherapy combination attacks brain tumors in stage 4 melanoma patients

Colleen Wittoesch learned in March 2016 that she had late-stage melanoma in the most difficult way.

"I couldn't get my thoughts together, I kept forgetting things," she recalls. "One night I was talking to my daughter and she said 'you don't sound right, we need to take you to the ER.'"

An MRI scan showed 12 tumors in her brain. A surgeon removed the two largest, which were applying pressure on her brain and affecting her thinking.

Wittoesch sought treatment at MD Anderson, where she had volunteered for 12 years, seven of those in the Melanoma clinic.

For stage IV melanoma that has spread to the brain, surgery and radiation can remove small tumors and provide relief from symptoms, but they don't stop disease progression. Median survival for these patients is four-to-five months.

Melanoma brain metastases are known to be resistant to multiple types of chemotherapies. In addition, due to the poor prognosis associated with melanoma brain metastases, patients often are excluded by drug companies from clinical trials.

In 2016, this had started to change, and Wittoesch's oncologist, Rodabe Amaria, M.D., an assistant professor of Melanoma Medical Oncology, enrolled her in a clinical trial of two immunotherapy drugs designed to free the immune system to attack cancer.

Not long after the three-month initial regimen of the drugs ipilimumab and nivolumab, Amaria had good news.

"I remember hearing her heels as she came down the hall to the clinic room," Wittoesch says. "She had tears in her eyes and said 'Colleen, there's nothing, absolutely nothing there. The cancer is gone.'"

That complete response has endured.

Results from Wittoesch's clinical trial were reported in August in the New England Journal of Medicine.

Remarkable results with immunotherapy combo

"Historically, fewer than 20 percent of these patients survive for one year. With the immunotherapy combination in this study, 82 percent have survived to one year," says study leader Hussein Tawbi, M.D., Ph.D., associate professor of Melanoma Medical Oncology.

Of 94 patients in the single-arm study, at a median follow-up of 14 months, 24 (26 percent) had a complete response with no sign of disease, 28 (30 percent) had a partial response and two (2 percent) had stable disease.

At nine months, 56 patients had no progression of their brain tumors. "The absence of progression for that long with brain metastases is remarkable," Tawbi says.

"This practice-changing study proved that you can start with immunotherapy first with these patients, tackling both brain and disease elsewhere in the body at the same time," Tawbi explains. "And it opens up new opportunities for development of systemic therapies for metastatic melanoma."

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. Normally, both checkpoints shut down T cells and block the anti-tumor immune response. Blocking the checkpoints allows T cells, white blood cells that serve as the targeted warriors of the immune system, to attack.

Patients previously excluded from clinical trials

One reason patients with brain metastases had been excluded from clinical trials is that the blood-brain barrier — tight vascular construction of blood vessels serving the brain — prevents drugs from reaching tumors. Since immunotherapy empowers T cells to attack tumors, rather than treating tumors directly, the immune system cells can cross the barrier. There were, however, concerns about immune-related side effects.

"We were quite concerned going into the study about immunotherapy causing inflammation and swelling in the brain, so this was closely monitored," Tawbi says. "In the end, only 5 percent of patients had swelling in the brain."

The most common brain-related side effect was headache, and most of these side effects were low grade and easily managed. Overall, 52 patients (55 percent) had more challenging side effects, with 19 patients (20 percent) having to leave the trial.

For Wittoesch, the main side effect of the treatment "was like having the flu. I was kind of shaky and sick at times."

The trial is a lifesaver

"I've never had chemotherapy, but I have seen it up close, and it can be pretty harsh," she says, referring to her experience as an MD Anderson volunteer and with her father's treatment years ago.

"Dealing with cancer can be such a difficult fight," she says. "Without this clinical trial, I wouldn't be here, and it's a great pleasure for me to know that this study will be used to help other people."

Tawbi notes oncologists continue to work with radiation oncologists and neurosurgeons to further improve outcomes and provide the best guidance for patients on initial treatment and the best timing for subsequent treatments, if needed.

"Helping 57 or 58 percent of these patients is significant improvement, but our goal is to reach 100 percent," Tawbi says.