Abstract
A phase I/II clinical trial suggests that dabrafenib shrinks or stabilizes low-grade gliomas in children with the BRAF V600E mutation. Objective, durable responses occurred in 38% of patients, and the side effects were less severe than with chemotherapy. The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib.
Dabrafenib (Tafinlar; Novartis) shrinks and stabilizes low-grade gliomas in children who carry the BRAF V600E mutation, according to data presented last month at the 2016 Congress of the European Society for Medical Oncology in Copenhagen, Denmark. On the strength of these findings, researchers have already launched a follow-up trial in children that will evaluate dabrafenib combined with another targeted therapy, trametinib (Mekinist; Novartis).
Children with low-grade gliomas commonly receive multiple lines of chemotherapy, including carboplatin, vincristine, and lomustine. Although these regimens are often successful—rates of long-term survival are as high as 90%—they can also trigger serious side effects such as kidney damage, hearing loss, and secondary leukemias. “The majority of kids are surviving, but we are doing a ton of damage to get them there,” says lead investigator Mark Kieran, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA.
Kieran and his colleagues wondered whether a targeted therapy would be less harmful. About 10% of children with low-grade gliomas carry the BRAF V600E mutation. Dabrafenib, a BRAF inhibitor, is FDA-approved for adult patients with melanoma who have this mutation. The drug also readily crosses the blood–brain barrier, Kieran notes.
The researchers evaluated dabrafenib in a phase I/II trial that included 32 children with relapsed or refractory low-grade gliomas. The objective response rate was 38%, including one complete response and 11 partial responses. An additional 14 patients had stable disease.
Dabrafenib's common side effects were milder than with chemotherapy and included fever, vomiting, rash, and fatigue. Three patients developed pneumonia. Squamous cell carcinomas have occurred in patients with melanoma who are given dabrafenib, but the team did not detect any cases of this cancer in the children in their study.
The combination of dabrafenib and trametinib, a MEK inhibitor, is another approved option for adult patients with BRAF-mutant inoperable or metastatic melanoma. Kieran and colleagues are now investigating these two drugs in a phase I/II clinical trial that includes children with low-grade gliomas or with other tumor types positive for BRAF V600E, such as malignant gliomas, Langerhans cell histiocytosis, and thyroid carcinoma. “If this combination works in these kids like it did in adults with melanoma, it would be even better,” he says.
These drugs stabilize rather than destroy tumors, says Tobey MacDonald, MD, of Emory University School of Medicine in Atlanta, GA, who wasn't connected to the study. Patients might thus have to stay on them for a lifetime, and their long-term effects are unclear. Nonetheless, he says, “it's extremely exciting and encouraging that these drugs could be effective agents that allow us to replace chemotherapy entirely” for pediatric glioma. –Mitch Leslie