Targeted Therapy Combination Shows Promising Antitumor Activity in Aggressive Meningiomas

PHILADELPHIA — The targeted therapy combination of the mTOR inhibitor everolimus (Afinitor) and the somatostatin agonist octreotide (Sandostatin) yielded promising antitumor activity and survival outcomes in patients with aggressive meningiomas, according to the results of a phase II trial published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

Meningiomas are the most common primary brain tumors in adults, representing 37 percent of the total. Standard treatment is surgery, followed by radiotherapy and radiosurgery for more aggressive tumors. “Aggressive meningiomas represent about 20 percent of tumors treated with surgery, and prognosis is poor for patients with tumors that progress following radiotherapy and radiosurgery,” said Thomas Graillon, MD, PhD, assistant professor of neurosurgery at La Timone Hospital in Marseille, France. Systemic therapies have failed to show clear signals of efficacy or substantial clinical benefit, he added.

“The combination of everolimus and octreotide yielded a meaningful, prolonged tumor stabilization in many patients,” noted Graillon. “Our results indicate that this combination treatment could be considered as a viable treatment option for aggressive meningiomas and studied further in a randomized trial.”

Meningiomas frequently demonstrate an activated mechanistic target of rapamycin (mTOR) pathway and express somatostatin receptor 2 (SSTRA2). Somatostatin is a hormone found in the central nervous system that inhibits the release of growth hormone. In previous preclinical research, Graillon and colleagues demonstrated that the combination of everolimus and octreotide had an additive antitumor effect in primary cell cultures derived from fresh operative tissue samples.

The CEVOREM (Combination of EVerolimus and Octreotide in REsistant Meningiomas) trial tested the effectiveness of everolimus and octreotide in 20 adults with mainly grades 2 or 3 meningiomas as defined by the World Health Organization (WHO). Two patients had grade 1 tumors, 10 had grade 2 tumors, and eight had grade 3 tumors. All patients received 10 mg of oral everolimus daily, and 30 mg of octreotide administered monthly by intramuscular injection.

Progression-free survival (PFS) at six months was 55 percent, meeting the study’s primary endpoint. “This significantly exceeds the typical rate of about 10-20 percent for patients with aggressive meningiomas who are ineligible for further surgery or radiosurgery,” Graillon said.

Six- and 12-month overall survival rates were 90 percent and 75 percent, respectively. The investigators also reported a decrease of more than 50 percent in the tumor growth rate in 78 percent of tumors at three months.

The drug combination was well tolerated in most patients, in line with current use among patients with pancreatic neuroendocrine tumors, Graillon noted. Eleven of 20 patients developed stomatitis, including three with grade 3 adverse events, requiring the discontinuation of everolimus in one patient and both drugs in another patient.

The investigators assessed tumor growth rate at enrollment (with a documented minimal growth rate for inclusion in the trial) and at three and six months after treatment using radiological methods, including 3D T1-weighted gadolinium-enhanced millimetric magnetic resonance imaging. “Our results suggest that analyzing the 3D tumor growth rate is a more appropriate method for assessing treatment activity in this select group of patients,” Graillon said. “3D tumor growth rate under versus before treatment is a sensitive and complementary endpoint to six-month PFS that should be included in future randomized trials.”

The main limitations of the study were the small number of patients and the non-randomization.

The study was led with Olivier Chinot, MD, and the neurooncology team, and was supported by Institut National du Cancer in France. Novartis Pharma of France provided the drugs used in the study. The authors declare no conflict of interest.