The following press release was distributed by the American Society for Radiation Oncology (ASTRO)

Phase 2 clinical trial finds ¹⁷⁷Lu-Dotatate may extend progression-free survival for patients with no other options to manage recurrent disease

WASHINGTON — A radiopharmaceutical therapy that has successfully extended progression-free survival for patients with neuroendocrine tumors shows early signs for delivering similar benefits to patients with difficult-to-treat meningioma, a type of brain tumor. The nonrandomized phase 2 study's findings were presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting. 

"We've found a therapy with a meaningful signal for effectiveness and safety for people with refractory meningioma, a condition with no standard treatment options," says Dr. Kenneth Merrell, lead researcher of the trial and a radiation oncologist at Mayo Clinic Comprehensive Cancer Center. "Nearly 80% of patients in our study were progression-free after six months. This rate greatly surpassed the benchmark from prior research, suggesting that radiopharmaceuticals are a promising therapeutic agent for these patients."

Meningiomas are tumors that grow in the connective tissue surrounding the brain and spinal cord. They are the most common type of primary brain tumor, and while they typically do not spread to other parts of the body, they can grow uncontrollably and lead to disabling and deadly compression of the nerves and brain.

Standard treatment for patients with meningiomas is either surgical removal or external beam radiation therapy when tumors grow in areas where surgery is too dangerous, such as close to the brain stem or spinal cord. However, for the portion of patients where the tumor grows despite these treatments, known as refractory meningioma, the tumors tend to behave more aggressively, and retreatment is difficult because radiation and surgery cannot be repeated frequently without greater risks.

"There is no standard of care or proven option for managing refractory meningioma. Many of these patients continue to experience aggressive tumor growth and significant related complications, and ultimately the illness may prove fatal. It is a very challenging prognosis to manage, and in many cases, we are left with only supportive measures," says Dr. Merrell.

Dr. Merrell and his colleagues investigated whether patients with refractory meningioma would benefit from theranostics, an approach that combines therapy with diagnostics for personalized internal delivery of radiation treatment. Theranostics leverages radiopharmaceuticals — specialized medicine containing radioactive material — to find cancer cells in the body and attack them with precise doses of radiation, without harming the surrounding healthy tissue. This dual-pronged approach offers patients a more tailored, and potentially more effective, treatment option.

While still an emerging treatment modality, radiopharmaceuticals are commonly used to treat thyroid cancer, metastatic cancer such as bone metastases from prostate cancer, and other types of tumors. For this trial, researchers looked specifically at ¹⁷⁷Lu-Dotatate, an FDA-approved radiopharmaceutical for neuroendocrine tumors, which share biological similarities with meningiomas.

"There have been many attempts at testing a variety of chemotherapies and other systemic agents for these patients. And others have looked at this option for therapy, but no one had completed a prospective trial for this patient population before ours," says Dr. Geoffrey Johnson, co-lead of the trial and a nuclear medicine physician at Mayo Clinic Comprehensive Cancer Center. "With advanced PET imaging, the theranostic approach to treatment helps us to select those patients most likely to benefit from molecularly targeted radiation directly to their tumor cells."

The researchers conducted a single-arm, phase 2 clinical trial at a large academic center, enrolling patients with refractory meningioma that had grown at a rate of 15% or more over a six-month period. During a three-year period beginning in April 2020, patients including 20 people with WHO grade 2 or 3 disease were enrolled into the study. The median patient age was 67, and nearly all (95%) had grade 2 meningiomas. Trial participants received four infusions of ¹⁷⁷Lu-Dotatate spaced eight weeks apart.

Six months after treatment, 78% of patients had not experienced further tumor progression, far exceeding the benchmark progression-free survival rate of 26% established by prior research. The median time before patients' cancer progressed was 11.5 months.

After one year, overall survival was 88.9%. No patients experienced life-threatening side effects, while 10 had severely low blood counts, one had grade 3 hepatitis and one had a grade 3 seizure possibly related to treatment. Five patients did not complete treatment due to tumor progression (n=2), adverse events possibly related to treatment (n=2) or other comorbidities (n-1).

"Most patients tolerated the treatment well," says Dr. Merrell. "It appears that ¹⁷⁷Lu-Dotatate is a safe and rational therapeutic choice with broad eligibility for patients with aggressively growing meningiomas, particularly as alternative therapy options are limited.

"As there is no current standard of care for these patients, our findings establish a new benchmark and may influence the treatment options available."

Review the abstract below for a complete list of authors, disclosures and funding.

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About ASTRO
The American Society for Radiation Oncology (ASTRO) is the largest radiation oncology society in the world, with more than 10,000 members who are physicians, nurses, biologists, physicists, radiation therapists, dosimetrists and other healthcare professionals who specialize in treating patients with radiation therapies. Radiation therapy contributes to 40% of global cancer cures, and more than a million Americans receive radiation treatments for cancer each year. For information on radiation therapy, visit RTAnswers.org. To learn more about ASTRO, visit their website and follow them on social media.

About Mayo Clinic Comprehensive Cancer Center 
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About Mayo Clinic
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Media contact:

• Kelley Luckstein, Mayo Clinic Communications, newsbureau@mayo.edu

Abstract, American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting

A prospective, phase II study of ¹⁷⁷Lu-Dotatate in patients with surgery- and radiation-refractory meningioma: Results of the WHO grade II/III cohort

K.W. Merrell,¹ D.R. Johnson,² K.O. Steinert,³ M. Ruff,⁴ W. Breen,¹ H.J. Gunn,³ D.H. Lachance,⁴ C.L. Goergen,³ E.S. Yan,¹ U. Sener,⁴ S. Kizilbash,⁵ J.H. Uhm,⁴ P.D. Brown,¹ N.N. Laack, II¹ and G.B. Johnson²; ¹Department of Radiation Oncology, Mayo Clinic, Rochester, MN, ²Mayo Clinic, Division of Nuclear Medicine, Rochester, MN, ³Mayo Clinic, Rochester, MN, ⁴Mayo Clinic, Department of Neurology, Rochester, MN, ⁵Mayo Clinic, Department of Medical Oncology, Rochester, MN

Purpose/Objective(s): Meningioma is the most frequently encountered brain tumor and typically managed with surgery and/or radiotherapy. However, recurrence rates for WHO grade II and III meningioma are reported as high as 40-80%, respectively. With each recurrence, safe and effective salvage options are quickly exhausted, leading to significant morbidity and mortality. As nearly all meningiomas express somatostatin receptors, we evaluated the efficacy of lutetium-177 (¹⁷⁷Lu)−Dotatate for refractory meningioma.

Materials/Methods: This is a single-arm, phase II clinical trial conducted at a single, large academic center. Eligible patients included those with surgery- and radiation-refractory meningioma with measurable disease and ≥ 15% growth over a 6-month period. ⁶⁸Ga-DOTATATE PET/MRI was performed and a Krenning score of ≥ 2 was required. The ¹⁷⁷Lu-Dotatate was delivered at a dose of 7.4 GBq (200 mCi) every 8 weeks for a total of 4 administrations. MRI brain was performed prior to each administration. The primary endpoint was progression-free survival at 6 months (PFS-6). Exceeding the established RANO historical benchmark of 26% for PFS-6 signaled a promising therapy. Secondary endpoints include PFS, overall survival (OS), and rates of adverse events (AEs) at least possibly related to the investigational agent. A separate WHO grade I cohort continues to enroll.

Results: From April 2020 to April 2023, 26 patients were screened and 20 met all eligibility requirements and were enrolled into the WHO grade II/ III cohort. The median age was 66.8 years (range = 38.9-85.0) and 95% had WHO grade II meningioma. ECOG PS was 0, 1, and 2 in 55%, 35%, and 10% of patients, respectively. A total of 40% of patients had a history of seizures and 65% had a history of neurologic deficit related to the refractory tumor, although only 15% were receiving corticosteroids at the time of enrollment. A Krenning score of 2, 3 and 4 was observed in 45%, 45%, and 10% of patients, respectively. PFS-6 and median PFS was 77.8% (95% CI = 52-94) and 10.7 months, respectively. Median survival was not reached. 1-year OS was 88.5% (95% CI = 47-96). There was no grade 4 or 5 AE attributable to treatment. A total of 10 patients experienced grade 3 hematologic AE with two patients experiencing grade 3 hepatitis (n = 1) and grade 3 seizure (n = 1), at least possibly attributed to treatment. 5 patients did not complete all 4 administrations due to possible treatment related AE (n = 2), tumor progression (n = 2), and other comorbidities (n = 1).

Conclusion: This phase II clinical trial met the primary endpoint of PFS-6 and represents a significant milestone for surgery- and radiation-refractory meningioma as one of the first prospectively evaluated systemic agents to yield substantial clinical efficacy, surpassing established clinical benchmarks with reasonable safety profile. The ¹⁷⁷Lu-Dotatate PFS appears as a safe and rational therapeutic choice with broad eligibility for the patient population under study, particularly as alternative therapy options are limited.

Author Disclosures: K.W. Merrell: Clinical trial funding based on effort; Varian, Galera, Novartis, AstraZeneca, Pfizer. Oversee global outreach and education programs; GACCF. D.R. Johnson: None. K.O. Steinert: None. M. Ruff: None. W. Breen: Compensation/Payment; GE Healthcare. H.J. Gunn: None. D.H. Lachance: None. C.L. Goergen: None. E.S. Yan: None. U. Sener: None. S. Kizilbash: paid to institution; Sichuan Honghe Biotechnology. Clinical trial funds paid to institutions: Orbus Therapeutics, Apollomics, Wayshine, Celgene, LOXO Oncology, Incyte, Nerviano Medical Sciences, CNS Pharmaceuticals, Aminex Therapeutics. Advisory Board; Servier, SK Life Sciences. J.H. Uhm: None. P.D. Brown: None. N.N. Laack: None. G.B. Johnson: Grant/research funding; Novartis, Clarity. Copyright/ Patent/License/Royalty; Perspective Therapeutics. CSO; Nucleus RadioPharma

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