NEW YORK – Novartis' somatostatin receptor-targeting radiopharmaceutical Lutathera (177Lu-Dotatate) demonstrated promising early activity in a Phase II clinical trial of certain advanced brain cancer patients, according to data presented during the American Society for Radiation Oncology (ASTRO) annual meeting.
Kenneth Merrell, a radiation oncologist at the Mayo Clinic, presented data from 20 patients with somatostatin receptor (SSRT)-expressing, grade II and III meningioma treated with Lutathera. To be eligible for the trial, patients' meningioma tumors had to have progressed following treatment with surgery and radiation, and patients' tumors had to express somatostatin receptors according to gallium-based PET imaging with Novartis' Netspot (68Ga-Dotatate). Specifically, patients needed to have a Krenning score of 2 or higher, meaning that the uptake of Netspot in tumor cells had to equal the liver's uptake, confirming SSRT expression.
Lutathera, which involves an SSRT-directed peptide agent linked to the cytotoxic isotope lutetium-177, is commercially available as a treatment for patients with SSRT-expressing gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
"Similar to neuroendocrine tumors, meningiomas express high levels of somatostatin receptor," Merrell said, noting that prior studies suggest 80 percent to 100 percent SSRT expression across all grades of meningiomas. "We hypothesize that [Lutathera] may provide specific and targeted radiation for refractory meningioma with broad applicability across all grade types."
The clinical trial that Merrell and his team conducted involved two cohorts. One cohort included patients with grade I meningioma, and the other included patients with grade 2 and 3 meningioma. Merrell shared data from the latter cohort during his ASTRO presentation.
Among the 20 patients who underwent treatment with Lutathera for their refractory meningiomas, Merrell noted that more than half — 55 percent — had Krenning scores above 2, meaning their brain tumors had greater SSRT expression than the minimum required to enroll.
The meningioma patients in the trial received a median of two prior courses or radiation, and 15 percent of them had received prior chemotherapy as well.
After six months, 77.8 percent of patients were alive without tumor progression, beating the six-month progression-free survival benchmark rate of 22.6 percent that investigators generally want new meningioma therapies to meet before they consider them beneficial. Although the study's primary endpoint was progression-free survival after six months, Merrell highlighted that after two years the progression-free survival rate still slightly exceeded the benchmark at 22.7 percent.
The median progression-free survival on Lutathera was 11.5 months. As for overall survival, Merrell shared that after one year 88.9 percent of patients were alive, and the same was true for 63.8 percent of patients after two years. The median overall survival was 27.8 months on Lutathera.
"I'm excited about this approach," said Lia Halasz, a radiation oncologist at the University of Washington's Fred Hutchinson Cancer Center, during a press conference on Tuesday. "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 really looking for other types of treatment."
Adverse events were generally manageable with Lutathera and were consistent with the side effects listed on the US Food and Drug Administration-approved label for the radiopharmaceutical for patients with GEP-NETs. "The drug demonstrates a reasonable safety profile for patients with central nervous system tumors," he said. Ten percent of patients experienced grade 3 or higher adverse events, one of whom had a seizure, and another had liver failure but was treated successfully.
During the media briefing, Hyun Kim, a radiation oncologist at the Siteman Cancer Center at Washington University in St. Louis, mentioned another adverse event concern. The pituitary gland in the brain, he said, is known to express SSRT, which raises questions as to whether there might be long-term adverse effects concerning patients' pituitary function.
All in all, though, researchers at ASTRO were eager to see if the outcomes of this small trial will translate into a new radiopharmaceutical treatment for patients with brain tumors. "Considering the limited alternative therapies, our results suggest that [Lutathera] may be considered as a rational therapeutic choice for patients matching the inclusion criteria," Merrell said.
Halasz noted that further research will be needed to validate these encouraging findings and that longer-term follow-up is needed to determine how long these responses last.
Kim also underscored that it will be important to study posttreatment dosimetry data available from the trial. "We want to see if the radiopharmaceuticals are going exactly [where they're] targeted and if we can optimize that," he said, adding that the SSRT expression cutoff of a Krenning score of 2 or more could "always be up for discussion" depending on treatment uptake data. There might also be an opportunity for what he called "personalized dosimetry" — meaning treating patients with individualized dosages of Lutathera based on their cancers' uptake of diagnostic PET imaging agents.
Merrell said he and his team will indeed look into dosimetry data next in the Phase II Lutathera trial. In the longer term, he said that larger, randomized Phase III trials will be important to better home in on Lutathera's efficacy in this patient population.