Targeted Therapy for BRAF Mutation in Craniopharyngioma

A Massachusetts General Hospital researcher recently published an article showing that targeted therapy with BRAF and MEK inhibitors can be safe and exceptionally effective against papillary craniopharyngiomas. These rare, benign primary brain tumors are often treated with surgery, radiation, or both. However, those treatments often cause significant side effects and long-term complications. The new study shows that BRAF and MEK inhibition can shrink these tumors with the potential for fewer long-term complications.

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"Craniopharyngiomas can cause significant clinical symptoms, including blindness, memory loss, and endocrine or hormonal dysfunction—both due to their location and standard-of-care treatment. Surgery and radiation can work. The challenge is that those treatments often lead to significant clinical sequelae and long-term complications," says Priscilla Brastianos, MD, a Mass General Cancer Center physician-scientist and director of the Central Nervous System Metastasis Center. "This study represents a paradigm shift for managing patients with craniopharyngiomas. Given these data, targeted therapy can now be considered for these patients."

The Need for New Options in Craniopharyngioma

Craniopharyngiomas develop near the pituitary gland and often involve the pituitary stalk. Although they are benign, they tend to be locally aggressive, often abutting the optic chiasm and interfering with vision. They also frequently affect pituitary function.

"Many patients have lifelong sequelae and never return to their pre-diagnosis functional status. Patients can experience blindness, memory loss, and hormonal dysfunction, which can lead to obesity, changes in menstruation, or an inability to get pregnant for women in their childbearing years. After radiation, there is also an increased risk of stroke," Dr. Brastianos says. "Many patients aren't able to go back to work after getting treatment for this condition. Craniopharyngiomas represent a significant unmet need in the brain tumor field."

The Brastianos Lab focuses on understanding genomic and molecular drivers of human brain tumors to inform the development of novel therapies. The lab, in collaboration with Sandro Santagata, MD, PhD's laboratory at Brigham and Women's Hospital, previously discovered BRAF gene mutations in 95% of papillary craniopharyngiomas, establishing that BRAF mutations are exceedingly common in this tumor type (published in Nature Genetics).

Based on those results, Mass General treated a patient with multiple recurrent papillary craniopharyngiomas with the BRAF inhibitor vemurafenib and kinase inhibitor cobimetinib. The approach achieved a tumor reduction of 85%, leading to a cooperative trial funded by the National Cancer Institute, within the Alliance for Clinical Oncology Trials Network.

Establishing the Efficacy of Targeted Therapy for Brain Tumors

A phase II study published in the NEJM aimed to examine the safety and efficacy of BRAF and MEK inhibition in patients with BRAF-mutated papillary craniopharyngiomas who had not undergone previous radiation therapy.

Sixteen patients received an oral combination of vemurafenib and cobimetinib in 28-day cycles. At a median follow-up of 22 months and after a median of eight cycles of treatment, 15 patients had a durable objective partial response or better.

The only patient who did not respond stopped treatment after eight days due to anaphylaxis and renal injury. In total, 12 patients had adverse events, including rash, hyperglycemia, and increased creatine kinase levels. Adverse events led to treatment discontinuation in three patients.

Tumors shrunk between 68% and 99%. At 12 months, progression-free survival was 87%; at 24 months, it was 58%.

"These results represent the highest response rate to date of systemic therapies in brain tumors. Targeted therapy works for this tumor type. It led to dramatic responses in 94% of the population and 100% of the patients who got one or more cycles of therapy," Dr. Brastianos says.

Looking ahead, she envisions several other avenues of inquiry.

"One of the next goals would be to see whether we can use noninvasive approaches to diagnose this tumor. Then patients may be able to avoid surgery altogether," she says. "We also want to explore how long to treat patients with the targeted therapy and whether and when they need radiation after the targeted therapy."

Continuing to Explore Ways to Target the BRAF Mutation

Mass General continues to lead the national clinical trial as it accrues a second cohort of patients with progressive disease after radiation. Dr. Brastianos encourages physicians to refer any patient with a craniopharyngioma, a BRAF mutation and progressive disease after radiation.

"The trial highlights the power of precision medicine for primary brain tumors. By finding the right drug target, we can move the needle for brain tumors, which is an area that's in desperate need of new treatments," Dr. Brastianos says. "This research also highlights the power of national multidisciplinary collaboration. We had investigators from radiation oncology, neurosurgery, neuropathology, neuroradiology, medical oncology, neuro-oncology from all over the country, all coming together to bring this innovative treatment to the clinic. Mass General is truly unique in the amazing scientists, physicians and translational investigators that we have here. We can take science from the bench to the bedside quickly. That made this research happen."

Learn more about the Brastianos Lab

Learn more about Mass General Cancer Center