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Use of an approved radionuclide therapy for difficult-to-treat meningioma was associated with substantially improved progression-free survival (PFS) compared with a historical benchmark, according to results of a small single-arm phase II trial.

Among 20 patients with surgery- and radiation-refractory intracranial tumors, treatment with lutetium (Lu)-177 dotatate (Lutathera) was associated with a 6-month PFS rate three times higher than a historical rate established a decade ago for patients with WHO grade II/III tumors (77.8% vs 26%, respectively).

Median PFS was 11.5 months, with one patient remaining progression free at 3.5 years, and the median overall survival (OS) reached 27.8 months, reported Kenneth Merrell, MD, of the Mayo Clinic in Rochester, Minnesota.

"This demonstrates a clinically meaningful outcome across a broad patient population with meningioma, marking a significant milestone for treatment-refractory meningioma," Merrell said during a press briefing at the American Society for Radiation Oncology (ASTRO) annual meeting in Washington, D.C.

"Considering the limited alternatives for these patients, our results support the use of lutetium dotatate as a rational therapeutic choice," he added.

"Meningiomas are hard to study," said ASTRO discussant Lia Halasz, MD, of the University of Washington and Fred Hutchinson Cancer Center in Seattle. "One reason they are harder to study is because there isn't necessarily a big response to new therapies, so you can't see it right away. Also, it is rare enough that in a single institution you may have very small numbers of patients to do a trial."

"It's important to comment that this trial is small, and we will need longer-term follow-up to see how long this really lasts, but in a space where we need innovation, I think it is very exciting that you had a 77.8% progression-free survival at 6 months when your benchmark was as low as 26%," she added.

About 25,000 cases of meningioma are diagnosed in the U.S. each year, and the central nervous system (CNS) malignancies represent the most common cause of primary brain tumors. Most patients are effectively treated with surgery and/or radiation, but a subset will progress. Recurrence rates are higher among patients with WHO grade II/III meningioma, leading to an increased risk of mortality.

"At the time of recurrence, the behavior of the meningioma is often more aggressive," Merrell said. "Patients will quickly exhaust therapeutic options with surgery and radiation, and at the moment there is no systemic therapy that is FDA approved."

A radionuclide agent, Lu-177 dotatate was approved by the FDA in 2018 for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) based on results from the NETTER-1 trial. As explained by Merrell, meningiomas -- as with GEP-NETs -- express high levels (80-100%) of somatostatin receptor 2 (SSTR2), and across all grade types.

"Therefore, we hypothesized that lutetium dotatate may provide specific and targeted radiation for refractory meningioma with broad applicability across all grade types," he said.

The researchers conducted a single-arm, phase II clinical trial at a single academic center, enrolling patients with treatment-refractory meningioma that had grown at a rate of 15% or more over a 6-month period. During a 3-year period beginning in April 2020, patients with WHO grade II/III disease were enrolled in the study.

Median patient age was 67 years, and 35% were female. Roughly two-thirds had existing neurological deficits and 60% had a history of seizures, but only 15% were on active corticosteroid therapy.

Nearly all (95%) had grade II meningiomas. Patients were heavily pretreated, with at least one prior surgery in all patients, a median of two prior courses of radiotherapy (range up to seven), and prior chemotherapy in 15%.

Trial participants received four infusions of Lu-177 dotatate spaced 8 weeks apart, with 70% receiving all four infusions.

The primary outcome was the estimated 6-month PFS with Lu-177 dotatate, with the drug considered of particular interest if that rate exceeded 35%. A of 47 studies published in 2014 had established a PFS benchmark of 26% for WHO grade II/III meningiomas.

The 2-year PFS rate was 26.7%, Merrell reported, while 1- and 2-year OS rates were 88.9% and 63.8%, respectively.

Grade 3 adverse events (AEs) occurred in two patients (one seizure and one hepatic failure). "We did not observe any cases of CNS radiation necrosis, even despite a very heavily pretreated patient population," Merrell said.

Regarding hematologic AEs, grade 3 lymphopenia occurred in 10 patients and grade 3 anemia in one patient. "Importantly, we did not observe any cases of myelodysplastic syndrome or acute myeloid leukemia," Merrell said.

During a press briefing where the study findings were presented, discussant Hyun Kim, MD, of the Washington University School of Medicine in St. Louis, noted that the grade 3 lymphopenia rate of 50% was much higher than the 9% rate reported in NETTER-1, and that further follow-up and evaluation long-term of myelodysplastic syndrome and renal dysfunction "will be interesting to see in this population."

Kim also questioned whether there could be an opportunity for personalized dosing with this regimen. "Can you give more and more Lutathera to these patients until you know from personalized dosimetry that there's no more room left, and see whether that increases PFS and survival?" he asked.

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