177Lu-Dotatate Shows Promise for Refractory Meningioma

WASHINGTON — A phase 2 study has demonstrated encouraging results for lutetium-177 (177Lu) dotatate in patients with surgery- and radiation-refractory meningioma.

Kenneth Merrell, MD, MS, presented the findings, which, he said, “offer new hope for patients with limited treatment options,” at the American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting.

Study Rationale

Meningiomas are the most common primary brain tumors. Although most are effectively managed with surgery, radiotherapy, or both, a subset of patients, particularly those with WHO grade 2 and 3 tumors, experience disease progression. Recurrence rates for these higher-grade meningiomas can reach 40%-80%, and treatment options become increasingly limited with each recurrence, said Merrell, who is a radiation oncologist at Mayo Clinic.

“Tumor behavior upon recurrence is often more aggressive, and patients may quickly exhaust safe and effective options for surgery and radiation,” Merrell explained during his presentation. “Currently, systemic therapy remains off-label and unproven.”

Study Design

The single-arm, phase 2 clinical trial conducted at Mayo Clinic enrolled 20 patients with surgery- and radiation-refractory WHO grade 2/3 meningioma. Eligible patients had measurable disease with at least 15% tumor growth over a 6-month period and a Krenning score ≥ 2 on Gallium-68 dotatate PET-MRI. The patient population was heavily pretreated, with all participants having undergone at least one prior surgery and a median of two previous courses of radiation (range up to seven). Merrell emphasized the challenging nature of this cohort, stating in his presentation, “Tumor behavior upon recurrence is often more aggressive, and patients may quickly exhaust safe and effective options for surgery and radiation.”

Commenting on the inclusion criteria used in this study, Hyun Kim, MD, associate professor of radiation oncology at Washington University School of Medicine in St. Louis, said: “The investigators allowed a Krenning score of ≥ 2, but in my practice and in many other practices, sometimes the cutoff of 3 is used. But for this patient population without a lot of treatment options, it was very reasonable to use 2 as a cutoff.”

Participants received 177Lu-dotatate at a dose of 7.4 GBq (200 mCi) every 8 weeks for a total of four administrations. The primary endpoint was progression-free survival (PFS) at 6 months, with a historical benchmark of 26% established by the Response Assessment in Neuro-Oncology (RANO) working group.

In an interview, Merrell explained the mechanism of action and rationale for testing 177Lu-dotatate in this population.

“177Lu-dotatate is a radiation treatment that is delivered via infusion rather than through an external source. The peptide component of the drug binds with high affinity to the somatostatin receptor 2 on the surface of the tumor, and the 177Lu is internalized into the cell.”

He added, “Since the dotatate is the same peptide in both imaging and therapy, we can predict prior to treatment whether the 177Lu is likely to be delivered to the tumor.”

PFS Benefit With 177Lu-Dotatate Reached

The primary endpoint of PFS at 6 months was met. The 6-month PFS rate was 77.8% (95% CI, 52%-94%), exceeding the historical benchmark of 26% established by the RANO working group. The median PFS was 11.5 months, and the 2-year PFS was 26.7% (95% CI, 12%-58%).

The 1-year overall survival (OS) rate was 88.9% (95% CI, 47%-96%), and the 2-year OS rate was 63.8% (95% CI, 44%-92%). The median OS was 27.8 months. Notably, five patients remained progression free at the time of reporting, with one patient maintaining stability for 3.5 years post-enrollment.

Safety of 177Lu-Dotatate

The treatment demonstrated a manageable safety profile, and no grade 4 or 5 adverse events (AEs) attributable to treatment were reported. The most common grade 3 hematologic AE was lymphocytopenia, occurring in 50% patients, consistent with the US Food and Drug Administration label for 177Lu-dotatate in other indications. Two patients (10%) experienced grade 3 nonhematologic AEs possibly related to treatment: One case of hepatitis and one seizure. Importantly, no cases of CNS radiation necrosis were observed despite the extensive prior radiation exposure in many patients.

“Most of these patients were heavily pretreated with all having at least one prior surgery and a median of two courses of external beam radiation,” Merrell noted in an interview.

He added, “Despite this, only 2 of the 20 patients discontinued drug therapy due to possible AEs related to the drug, supporting the safety profile of the drug.”

Implications for Clinical Practice

In an interview, Merrell emphasized the significance of these findings.

“This phase 2 clinical trial met its primary endpoint, with 177Lu-dotatate surpassing the historical benchmark of 26% and achieving a 6-month PFS of 77.8%. This demonstrates clinically meaningful outcomes across a broad patient population with meningioma, marking a significant milestone for the treatment of refractory meningioma.”

While 177Lu-dotatate shows promise, Merrell cautioned against considering it as a first-line treatment at this stage.

“Our trial design focused on the patient population where we saw the greatest unmet need, which is treatment-refractory meningioma,” he said in an interview. “There is no evidence now to support the drug in the first-line setting for WHO grade 2 or 3 meningioma.”

Lia M. Halasz, MD, professor at the University of Washington School of Medicine, Seattle, commented on the significance of the study during a media briefing.

“I’m excited about this innovative approach because we all have patients who have been treated multiple times with surgery and radiation therapy and you get to a point where those are no longer helpful, and you’re looking for other types of treatment,” she said.

Future Directions

Halasz, who was not involved in the study, emphasized that the findings need to be confirmed in larger studies.

“It’s important to note that this trial is small, with only 20 patients. We need longer-term follow-up to see how long this [effect] lasts,” she said.

“We are excited in the future to see any post-treatment dosimetry that may be available,” said Kim during the briefing. “We want to see if the radiopharmaceuticals are going exactly as targeted and if we can optimize that.”

Kim, who was not involved in the study, also raised the following questions about potential long-term effects and personalized dosing.

“Is there going to be long-term pituitary effects, and is there any opportunity for personalized dosing? Can we give more 177Lu-dotatate to these patients to see if this increases the PFS and survival?”

Merrell discussed future research directions in an interview.

“We are focusing on the exploratory endpoints of the trial, including a detailed dosimetry evaluation to understand the amount of radiation delivered to the tumor. This may offer insight into why some patients had a longer duration of response than others and perhaps could influence future dosing of the drug.”

“Further validation of our results is very important, and we are eager to collaborate and develop larger-scale clinical trials,” he added.

Merrell reported financial relationships with Novartis, AstraZeneca, Varian, and Galera Therapeutics (research and clinical trial funding); Mayo Clinic (employment); Pfizer and Varian (Global Education funding); Global Bridges Oncology (medical director); and Global Access to Cancer Care Foundation (Board of Directors). Kim reported financial relationships with Washington University School of Medicine (employment); Novartis (consultation fees); Varian and ViewRay (research funding); Varian and ViewRay (honoraria); GlobalART (ownership); and IJROBP (associate editor). Halasz reported financial relationships with the University of Washington (employment), UptoDate (consultation fees), and BioMimetix and Kuni Foundation (research funding).